Steroid hormone compositions in medium chain oils

ABSTRACT

This disclosure provides a novel pharmaceutical composition capable of forming micelles upon exposure to the gastric environment. The pharmaceutical composition is suitable for delivering steroid hormones, and progesterone in particular, to a subject in need thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/317,056, entitled “STEROID HORMONE COMPOSITIONS IN MEDIUM CHAINOILS,” filed on Apr. 1, 2016, the entirety of which is herebyincorporated by reference.

FIELD

This disclosure relates to the field of steroid hormones and inparticular, provides a pharmaceutical composition comprising afully-solubilized steroid hormone having enhanced oral bioavailabilitycompared with currently marketed pharmaceutical compositions.

BACKGROUND

Steroid hormones are vital constituents for the proper functioning ofthe human body and can be classified into five groups based on thereceptors to which they bind, namely: glucocorticoids,mineralocorticoids, androgens, estrogens, and progestogens. It is knownthat steroid hormones aid in regulating metabolism, regulating water andsalt function, regulating immune function, controlling inflammation, anddeveloping sexual characteristics.

Despite their wide ranging biological activity, steroid hormones aredifficult to deliver to a subject experiencing a disease or disorderwhere additional steroid hormone could help treat the disease ordisorder. Progesterone, for example, has extremely poor oralbioavailability due to its limited water solubility. As a result, whengiven orally, it must be administered in a sufficiently high dose toobtain the desired pharmacokinetic profile. Higher dosages, however, areinherently less desirable as the greater the quantity dosed, the greaterthe risk that additional drug, beyond what the patient requires, couldenter the bloodstream.

Progesterone is a naturally occurring C-21 steroid hormone belonging tothe progestogen class. It is produced by the cells of the corpus luteumduring the post-ovulatory luteal phase and to a lesser degree by theadrenal glands and the placenta during the second part of pregnancy. Inwomen, progesterone levels are relatively low during the pre-ovulatoryphase of the menstrual cycle, rise after ovulation, and are elevatedduring the luteal phase. Progesterone is commonly referred to as the“hormone of pregnancy” as it plays an important role in fetaldevelopment. Further, progesterone insufficiency can lead topremenstrual syndromes and menstrual irregularities.

Progesterone is used to support pregnancy in Assisted ReproductiveTechnology (ART) cycles, to control persistent ovulatory bleeding, toprepare the uterine lining in infertility therapy, and to support earlypregnancy. Further, progesterone can be used for regularizingmenstruation.

Progesterone is also used to oppose uterine hyperplasia and uterinecancer in women who are treating the symptoms of menopause with estrogentherapies.

Because progesterone does not dissolve in water and is poorly absorbed,currently marketed oral progesterone dosage forms administered topatients result in both intra- and inter-patient variability. Toovercome the drawbacks of poor bioavailability associated with naturalprogesterone, researchers have used various synthetic progesteronederivatives such as medroxyprogesterone, norethisterone,methylestrenolone, chlormadinone acetate, 6-dehydroretroprogesterone,and lynestrenol. But, use of these derivatives is associated withside-effects not associated with natural progesterone.

SUMMARY

This disclosure is directed to pharmaceutical compositions capable offully solubilizing a steroid hormone and that form micelles uponadministration. The pharmaceutical compositions comprise a steroidhormone, various medium chain oils, a polysorbate, and, optionally, aterpene. In certain embodiments, the steroid hormone can be aprogestogen, such as progesterone. In certain embodiments, the mediumchain oils are predominantly C6-C14 medium chain oils. In certainembodiments, the optional terpene can be a monocyclic terpene such asd-limonene. In certain embodiments, the pharmaceutical compositioncomprises, in addition to the progesterone, a bio-identical estrogen. Incertain embodiments, the estrogen is estradiol. The pharmaceuticalcompositions provide oral bioavailability, as measured by AUC, of thesteroid hormone, which in certain embodiments is progesterone, of atleast 125%, at least 150%, at least 175%, and in certain instances, atleast 200% relative to a reference product such as PROMETRIUM.

This disclosure further provides methods of treating, inhibiting, orpreventing a condition or disorder characterized by a steroid hormonedeficiency, and in particular, conditions or disorders characterized bylow levels of one or more steroid hormones, and particularlyprogesterone. The methods comprise administering to a subject atherapeutically effective amount of at least one pharmaceuticalcomposition described herein.

In one embodiment, the present disclosure provides a pharmaceuticalcomposition for providing enhanced oral bioavailability of progesterone,the pharmaceutical composition comprising: progesterone, a polysorbate,and a medium chain oil, wherein the medium chain oil comprises at leastabout 50 weight percent of a predominantly medium chain monoglyceride;and the progesterone is fully solubilized.

In certain embodiments, the medium chain oil comprises at least about 55weight percent of a predominantly medium chain monoglyceride.

In other embodiments, the medium chain oil comprises at least about 60weight percent of a predominantly medium chain monoglyceride.

In certain embodiments the medium chain oil comprises at least about 65weight percent of a predominantly medium chain monoglyceride.

In certain embodiments, the medium chain oil comprises at least about 70weight percent of a predominantly medium chain monoglyceride.

In certain embodiments, the polysorbate is selected from the groupconsisting of polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 65, and polysorbate 80.

In certain embodiments, the pharmaceutical composition provides an oralbioavailability of at least about 150 percent as measured by an increasein AUC when compared to a reference product.

In certain embodiments, the pharmaceutical composition further comprisesa polyoxyethylene hydrogenated castor oil.

In certain embodiments, the pharmaceutical composition further comprisesa d-α-tocopherol polyethylene glycol succinate derivative.

In certain embodiments, the pharmaceutical composition further comprisesa terpene.

In certain embodiments, the predominantly medium chain monoglyceride andthe progesterone can be present at a weight ratio of about 10:1 to about15:1.

In certain embodiments, the predominantly medium chain monoglyceridecomprises at least about 60 weight percent of the medium chain oil.

In certain embodiments, the predominantly medium chain monoglyceridecomprises at least about 70 weight percent of the medium chain oil.

In certain embodiments, the predominantly medium chain monoglyceridecomprises at least about 80 weight percent of the medium chain oil.

In certain embodiments, the predominantly medium chain monoglyceridecomprises at least about 90 weight percent of the medium chain oil.

In certain embodiments, the polysorbate is selected from the groupconsisting of polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 65, and polysorbate 80.

In certain embodiments, the pharmaceutical composition provides an oralbioavailability of at least about 150 percent as measured by an increasein AUC when compared to a reference product.

In certain embodiments, the pharmaceutical composition further comprisesa polyoxyethylene hydrogenated castor oil.

In certain embodiments, the pharmaceutical composition further comprisesa d-α-tocopherol polyethylene glycol succinate derivative.

In certain embodiments, the pharmaceutical composition further comprisesa terpene.

In certain embodiments, the present disclosure provides an oral,fully-solubilized progesterone pharmaceutical composition comprising:progesterone and a polysorbate in a weight ratio of from about 1:2 toabout 2:1; and a medium chain oil comprising a mixture of medium chainmono- and diglycerides, the medium chain oil not containing more thanabout 10 weight percent triglycerides.

In certain embodiments, the polysorbate is selected from the groupconsisting of polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 65, and polysorbate 80.

In certain embodiments, the pharmaceutical composition provides an oralbioavailability of at least about 150 percent as measured by an increasein AUC when compared to a reference product.

In certain embodiments, the pharmaceutical composition further comprisesa polyoxyethylene hydrogenated castor oil.

In certain embodiments, the pharmaceutical composition further comprisesa d-α-tocopherol polyethylene glycol succinate derivative.

In certain embodiments, the pharmaceutical composition further comprisesa terpene.

In other embodiments, the present disclosure provides a method oftreating a disease or condition associated with reduced progesteronelevels, the method comprising administering to a subject in need thereofa pharmaceutical composition comprising: progesterone, a polysorbate,and a medium chain oil, wherein the medium chain oil comprises at leastabout 50 weight percent of a predominantly medium chain monoglyceride;and the progesterone is fully solubilized.

In certain embodiments, the method comprising administering to a subjectin need thereof a pharmaceutical composition comprising: progesteroneand a polysorbate in a weight ratio of from about 1:2 to about 2:1; anda medium chain oil comprising a mixture of medium chain mono- anddiglycerides, the medium chain oil not containing more than about 10weight percent triglycerides.

In certain embodiments, the disease or condition associated with reducedprogesterone levels is selected from the group consisting of endometrialhyperplasia; secondary amenorrhea; prevention of preterm birth; andosteoporosis.

In certain embodiments, the disease or condition associated with reducedprogesterone levels is menopause.

In addition to the foregoing, the present disclosure also provides apharmaceutical composition for providing enhanced oral bioavailabilityof progesterone, the pharmaceutical composition comprising:progesterone, a polysorbate, and a medium chain oil, wherein the mediumchain oil comprises at least about 50 weight percent of a first mediumchain oil component; and the progesterone is fully solubilized.

In some embodiments, the medium chain oil further comprises a secondmedium chain oil component.

In some embodiments, the first medium chain oil component is apredominantly medium chain monoglyceride.

In some embodiments, the second medium chain oil component is apredominantly medium chain diglyceride.

In some embodiments, the predominantly medium chain diglyceride is amixed or complex diglyceride.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

The foregoing summary, as well as the following detailed description,will be better understood when read in conjunction with the appendedfigures. For the purpose of illustration, the figures may describe theuse of specific embodiments. It should be understood, however, that thisdisclosure is not limited to the precise embodiments discussed ordescribed in these figures.

FIG. 1 is a graph of plasma concentration of progesterone vs. time forrats dosed with 20 μl of each of the various embodiments of thepharmaceutical composition described herein or 20 μl PROMETRIUM. Becauseof the way it is formulated, PROMETRIUM contains 400 mg progesterone/gof formulation. As such, the amount of progesterone dosed in ratstreated with 20 μl PROMETRIUM far exceeded the amount of progesteronedelivered to rats treated with 20 μl of the pharmaceutical compositionsof this disclosure.

FIG. 2 is the log-linear version of FIG. 1.

FIG. 3 is a graph of plasma concentration of progesterone metaboliteallopregnanolone sulfate vs. time for various embodiments of thepharmaceutical composition described herein and PROMETRIUM. As discussedabove, the amount of progesterone administered to rats treated with 20μl PROMETRIUM far exceeded the amount of progesterone administered torats treated with 20 μl of the pharmaceutical compositions of thisdisclosure.

FIG. 4 is a log-linear version of FIG. 3.

FIG. 5 is a graph of plasma concentration of progesterone metabolite20α-dihydroprogesterone vs. time for various embodiments of thepharmaceutical composition described herein and PROMETRIUM. As discussedabove, the amount of progesterone administered to rats treated with 20μl PROMETRIUM far exceeded the amount of progesterone administered torats treated with 20 μl of the pharmaceutical compositions of thisdisclosure.

FIG. 6 is a log-linear version of FIG. 5.

FIG. 7 is a graph of the plasma concentration of progesterone vs. timefor fed and fasted rats dosed with 20 μl (25 mg/kg sample) ofPROMETRIUM.

FIG. 8 is a graph of the plasma concentration of progesterone vs. timefor fed and fasted rats dosed with 20 μl (3.7 mg/kg progesterone) oftest pharmaceutical composition D in a gavage micro capsule.

FIG. 9 is a graph of the plasma concentration of progesterone vs. timefor fed and fasted rats dosed with 20 μl (3.7 mg/kg progesterone) oftest pharmaceutical composition C in a gavage micro capsule.

FIG. 10 is a graph of the plasma concentration of progesterone vs. timefor fed and fasted rats dosed with 20 μl (3.7 mg/kg progesterone) oftest pharmaceutical composition A in a gavage micro capsule.

FIG. 11 is graph of plasma concentration of progesterone vs. time forPROMETRIUM and test pharmaceutical composition D.

DETAILED DESCRIPTION Definitions

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise.

As used herein, the term “or” is a logical disjunction (i.e., and/or)and does not indicate an exclusive disjunction unless expresslyindicated as such with the terms “either,” “unless,” “alternatively,”and words of similar effect.

The term “area under the curve” (“AUC”) refers to the area under thecurve defined by changes in the blood concentration of an activepharmaceutical ingredient (e.g., progesterone or estradiol), or ametabolite of the active pharmaceutical ingredient, over time followingthe administration of a dose of the active pharmaceutical ingredient.“AUC_(0-∞)” is the area under the concentration-time curve extrapolatedto infinity following the administration of a dose. “AUC_(0-t)” is thearea under the concentration-time curve from time zero to time tfollowing the administration of a dose, wherein t is the last time pointwith a measurable concentration.

The term “C_(max)” refers to the maximum value of blood concentrationshown on the curve that represents changes in blood concentrations of anactive pharmaceutical ingredient (e.g., progesterone or estradiol), or ametabolite of the active pharmaceutical ingredient, over time.

The term “t_(max)” refers to the earliest time at which the bloodconcentration of an active pharmaceutical ingredient (e.g., progesteroneor estradiol), or a metabolite of the active pharmaceutical ingredientis at its maximum value.

The term “bioavailability,” which has the meaning defined in 21 C.F.R. §320.1(a), refers to the rate and extent to which an active ingredient oractive moiety is absorbed from a drug product and becomes available atthe site of action. For drug products that are not intended to beabsorbed into the bloodstream, bioavailability may be assessed bymeasurements intended to reflect the rate and extent to which the activeingredient or active moiety becomes available at the site of action. Forexample, bioavailability can be measured as the amount of activeingredient in the blood (serum or plasma) as a function of time.Pharmacokinetic (PK) parameters such as AUC, C_(max), or t_(max) may beused to measure and assess bioavailability.

The term “bioequivalent,” has the meaning defined in 21 C.F.R. §320.1(e) and refers to the absence of a significant difference in therate and extent to which the active ingredient or active moiety inpharmaceutical equivalents or pharmaceutical alternatives becomesavailable at the site of drug action when administered at the same molardose under similar conditions in an appropriately designed study. Wherethere is an intentional difference in rate (e.g., in certain extendedrelease dosage forms), certain pharmaceutical equivalents oralternatives may be considered bioequivalent if there is no significantdifference in the extent to which the active ingredient or moiety fromeach product becomes available at the site of drug action. This appliesonly if the difference in the rate at which the active ingredient ormoiety becomes available at the site of drug action is intentional andis reflected in the proposed labeling, is not essential to theattainment of effective body drug concentrations on chronic use, and isconsidered medically insignificant for the drug. In practice, twoproducts are considered bioequivalent if the 90% confidence interval ofthe AUC or C_(max) is within 80.00% to 125.00%.

The term “bio-identical hormone” refers to an active pharmaceuticalingredient that is structurally identical to a hormone naturally orendogenously found in the human body (e.g., progesterone or estradiol).

As used herein, the term “about” refers to ±10% of the noted value,unless otherwise specified, and unless the upper bound of the rangewould exceed 100% of the pharmaceutical composition, in which case theupper limit of the range is limited to 99.9%. Thus, and by way ofexample only, a pharmaceutical composition including about 10 weightpercent of a given compound could have from 9 to 11 weight percent ofthe compound. Similarly, a pharmaceutical composition including about 95weight percent of a given compound could have from 85.5 to 99.9 weightpercent of the compound in the pharmaceutical composition.

The term “estradiol” refers to (17β)-estra-1,3,5(10)-triene-3,17-diol.Estradiol is also interchangeably called 17β-estradiol, oestradiol, orE2, and is found endogenously in the human body. As used herein,estradiol refers to the bio-identical or body-identical form ofestradiol found in the human body having the structure:

Estradiol is supplied in an anhydrous or hemi-hydrate form. For thepurposes of this disclosure, the anhydrous form or the hemihydrate formcan be substituted for the other by accounting for the water or lack ofwater according to well-known and understood techniques.

The term “solubilized estradiol” means that the estradiol or a portionthereof is solubilized or dissolved in the solubilizing agent(s) or thepharmaceutical compositions disclosed herein. Solubilized estradiol mayinclude estradiol that is about 80% solubilized, about 85% solubilized,about 90% solubilized, about 95% solubilized, about 96% solubilized,about 97% solubilized, about 98% solubilized, about 99% solubilized orabout 100% solubilized. In some embodiments, the estradiol is “fullysolubilized” with all or substantially all of the estradiol beingsolubilized or dissolved in the solubilizing agent. Fully solubilizedestradiol may include estradiol that is about 97% solubilized, about 98%solubilized, about 99% solubilized or about 100% solubilized. Solubilitycan be expressed as a mass fraction (% w/w, which is also referred to aswt %).

The term “glyceride” refers to an ester of glycerol (1,2,3-propanetriol)with acyl radicals of fatty acids and is also known as an acylglycerol.If only one position of the glycerol molecule is esterified with a fattyacid, a “monoglyceride” or “monoacylglycerol” is produced; if twopositions are esterified, a “diglyceride” or “diacylglycerol” isproduced; and if all three positions of the glycerol are esterified withfatty acids, a “triglyceride” or “triacylglycerol” is produced. Aglyceride is “simple” if all esterified positions contain the same fattyacid; whereas a glyceride is “mixed” if the esterified positions aresubstituted with different fatty acids. A glyceride is “complex” if itcontains a combination of simple and mixed glycerides. The carbons ofthe glycerol backbone are designated sn-1, sn-2 and sn-3, with sn-2being the middle carbon and sn-1 and sn-3 being the end carbons of theglycerol backbone.

As used herein, the term “hormone deficiency” refers to a low level ofone or more steroid hormones in a subject. Normal hormone levels willvary from subject to subject and can be determined via known methods.Low hormone levels may or may not be associated with symptoms including,but not limited to, fatigue, irregular bleeding, lowered libido, anddepression. Conditions associated with progesterone deficiency includeendometrial hyperplasia; secondary amenorrhea; prevention of pretermbirth; menopause-related symptoms including, for example, vasomotorsymptoms (e.g., hot flashes and night sweats); in relation to treatmentof hypoestrogenism related symptoms including, for example and withoutlimitation, vasomotor symptoms, sleep disturbances, mood changes, andvulvovaginal atrophy; and osteoporosis and other non-menopausal diseasestates or conditions treated with supplemental progesterone.

As used herein, the terms “host,” “subject,” and “patient” refer to anyanimal, including humans.

As used herein, the term “prevent” refers to the prophylactic treatmentof a subject who is at risk of developing a condition (e.g., steroidhormone deficiency) resulting in a decrease in the probability that thesubject will develop the condition.

The term “progesterone” refers to pregn-4-ene-3,20-dione. Progesteroneis also interchangeably called P4 and is found endogenously in the humanbody. As used herein, progesterone refers to the bio-identical orbody-identical form of progesterone found in the human body and havingthe structure:

The term “solubilized progesterone” means that the progesterone or aportion thereof is solubilized or dissolved in the compositionsdisclosed herein. Solubilized progesterone may include progesterone thatis about 80% solubilized, about 85% solubilized, about 90% solubilized,about 95% solubilized, about 96% solubilized, about 97% solubilized,about 98% solubilized, about 99% solubilized or about 100% solubilized.In some embodiments, the progesterone is “fully solubilized” with all orsubstantially all of the progesterone being solubilized or dissolved ina given composition. Fully solubilized progesterone may includeprogesterone that is about 97% solubilized, about 98% solubilized, about99% solubilized or about 100% solubilized. Solubility can be expressedas a mass fraction (% w/w, which is also referred to as weight percent(wt %)).

The terms “micronized progesterone” and “micronized estradiol,” as usedherein, include micronized progesterone and micronized estradiol havingan X50 particle size value below about 15 microns or having an X90particle size value below about 25 microns. The term “X50” means thatone-half of the particles in a sample are smaller in diameter than agiven number. For example, micronized progesterone having an X50 of 5microns means that, for a given sample of micronized progesterone,one-half of the particles have a diameter of less than 5 microns.Similarly, the term “X90” means that ninety percent (90%) of theparticles in a sample are smaller in diameter than a given number.

The term “solubilizing agent” refers to an agent or combination ofagents that solubilize an active pharmaceutical ingredient (e.g.,progesterone or estradiol). For example and without limitation, suitablesolubilizing agents include medium chain oils and other solvents andco-solvents that solubilize or dissolve an active pharmaceuticalingredient to a desirable extent. Solubilizing agents suitable for usein the pharmaceutical compositions disclosed herein are pharmaceuticalgrade solubilizing agents (e.g., pharmaceutical grade medium chainoils). It will be understood by those of skill in the art that otherexcipients or components can be added to or mixed with the solubilizingagent to enhance the properties or performance of the solubilizing agentor resulting pharmaceutical composition. Examples of such excipientsinclude, but are not limited to, surfactants, emulsifiers, thickeners,colorants, flavoring agents, terpenes, etc. In some embodiments, thesolubilizing agent is a medium chain oil and, in some other embodiments,the medium chain oil is combined with a co-solvent(s) or otherexcipient(s).

The term “medium chain” is used to describe the aliphatic chain lengthof fatty acid containing molecules. “Medium chain” specifically refersto fatty acids, fatty acid esters, or fatty acid derivatives thatcontain fatty acid aliphatic tails or carbon chains that contain, forexample, 6 to 14 carbon atoms, 8 to 12 carbon atoms, or 8 to 10 carbonatoms.

The terms “medium chain fatty acid” and “medium chain fatty acidderivative” are used to describe fatty acids or fatty acid derivativeswith aliphatic tails (i.e., carbon chains) having 6 to 14 carbon atoms.Fatty acids consist of an unbranched or branched aliphatic tail attachedto a carboxylic acid functional group. Fatty acid derivatives include,for example, fatty acid esters and fatty acid containing molecules,including, without limitation, mono-, di- and triglycerides that includecomponents derived from fatty acids. Fatty acid derivatives also includefatty acid esters of ethylene or propylene glycol. The aliphatic tailscan be saturated or unsaturated (i.e., the latter having one or moredouble bonds between carbon atoms). In some embodiments, the aliphatictails are saturated (i.e., no double bonds between carbon atoms). Mediumchain fatty acids or medium chain fatty acid derivatives include thosewith aliphatic tails having 6-14 carbons, including those that areC6-C14, C6-C12, C8-C14, C8-C12, C6-C10, C8-C10, or others. Examples ofmedium chain fatty acids include, without limitation, caproic acid,caprylic acid, capric acid, lauric acid, myristic acid, and derivativesthereof. In certain embodiments, the medium chain fatty acids used toprepare the various medium chain oils described herein are C8, C10, or acombination thereof.

The term “oil,” as used herein, refers to any pharmaceuticallyacceptable oil, especially medium chain oils, and specifically excludingpeanut oil, that can suspend or solubilize bioidentical progesterone orestradiol, including starting materials or precursors thereof, includingmicronized progesterone and/or micronized estradiol as described herein.

The terms “treat,” “treating,” “treatment” and the like refer to anyindicia of success in the treatment or amelioration of an injury,disease, or condition, including any objective or subjective parametersuch as abatement; remission; diminishing of symptoms or making theinjury, disease, or condition more tolerable to the patient; slowing inthe rate of degeneration or decline; or improving a patient's physicalor mental well-being. The treatment or amelioration of symptoms can bebased on objective or subjective parameters, including the results of aphysical examination, neuropsychiatric examinations, or psychiatricevaluation.

The term “medium chain oil” refers to an oil wherein the composition ofthe fatty acid fraction of the oil is substantially medium chain (i.e.,C6 to C14) fatty acids, i.e., the composition profile of fatty acids inthe oil is substantially medium chain. As used herein, “substantially”means that between 20% and 100% (inclusive of the upper and lowerlimits) of the fatty acid fraction of the oil is made up of medium chainfatty acids, i.e., fatty acids with aliphatic tails (i.e., carbonchains) having 6 to 14 carbons. In some embodiments, about 25%, about30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%,about 65%, about 70%, about 75%, about 85%, about 90% or about 95% ofthe fatty acid fraction of the oil is made up of medium chain fattyacids. Those of skill in the art will readily appreciate that the terms“alkyl content” or “alkyl distribution” of an oil can be used in placeof the term “fatty acid fraction” of an oil in characterizing a givenoil or solubilizing agent, and these terms are used interchangeablyherein. As such, medium chain oils suitable for use in thepharmaceutical compositions disclosed herein include medium chain oilswherein the fatty acid fraction of the oil is substantially medium chainfatty acids, or medium chain oils wherein the alkyl content or alkyldistribution of the oil is substantially medium chain alkyls e.g.,C6-C14 alkyls, but also including, for example, C6-C12 alkyls, C8-C12alkyls, and C8-C10 alkyls. It will be understood by those of skill inthe art that the medium chain oils suitable for use in thepharmaceutical compositions disclosed herein are pharmaceutical grade(e.g., pharmaceutical grade medium chain oils). Examples of medium chainoils include, for example and without limitation, medium chain fattyacids, medium chain fatty acid esters of glycerol (e.g., for example,mono-, di-, and triglycerides), medium chain fatty acid esters ofpropylene glycol, medium chain fatty acid derivatives of polyethyleneglycol, and combinations thereof.

The term “ECN” or “equivalent carbon number” means the sum of the numberof carbon atoms in the fatty acid chains of an oil, and can be used tocharacterize an oil as, for example, a medium chain oil or a long-chainoil. For example, tripalmitin (tripalmitic glycerol), which is a simpletriglyceride containing three fatty acid chains of 16 carbon atoms, hasan ECN of 3×16=48. Conversely, a triglyceride with an ECN=40 may have“mixed” fatty acid chain lengths of 8, 16, and 16; 10, 14, and 16; 8,14, and 18; etc. Naturally occurring oils are frequently “mixed” withrespect to specific fatty acids, but tend not to contain both long chainfatty acids and medium chain fatty acids in the same glycerol backbone.Thus, triglycerides with ECN's of 21-42 typically contain predominatelymedium chain fatty acids; while triglycerides with ECN's of greater than43 typically contain predominantly long chain fatty acids. For example,the ECN of corn oil triglyceride in the USP would be in the range of51-54. Medium chain diglycerides with ECN's of 12-28 will often containpredominately medium chain fatty chains, while diglycerides with ECN'sof 32 or greater will typically contain predominately long chain fattyacid tails. Monoglycerides will have an ECN that matches the chainlength of the sole fatty acid chain. Thus, monoglyceride ECN's in therange of 6-14 contain mainly medium chain fatty acids, andmonoglycerides with ECN's 16 or greater will contain mainly long chainfatty acids.

The average ECN of a medium chain triglyceride oil is typically 21-42.For example, as listed in the US Pharmacopeia (USP), medium chaintriglycerides have the following composition as the exemplary oil setforth in the table below:

Fatty-acid % of Exemplary Tail Length oil Oil  6 ≤2.0 2.0  8 50.0-80.070.0 10 20.0-50.0 25.0 12 ≤3.0 2.0 14 ≤1.0 1.0and would have an average ECN of3*[(6*0.02)+(8*0.70)+(10*0.25)+(12*0.02)+(14*0.01)]=25.8. The ECN of theexemplary medium chain triglycerides oil can also be expressed as arange (per the ranges set forth in the USP) of 24.9-27.0. For oils thathave mixed mono-, di-, and triglycerides, or single and double fattyacid glycols, the ECN of the entire oil can be determined by calculatingthe ECN of each individual component (e.g., C8 monoglycerides, C8diglycerides, C10 monoglycerides, and C10 diglycerides) and taking thesum of the relative percentage of the component multiplied by the ECNnormalized to a monoglyceride for each component. For example, an oilhaving C8 and C10 mono- and diglycerides shown in the table below has anECN of 8.3, and is thus a medium chain oil.

Fatty-acid ECN as % of oil ECN as % of oil Chain % (chain length) ×normalized to Length of oil (% in oil) monoglyceride C8 monoglyceride 478 × 0.47 = 3.76 3.76 C10 monoglyceride 8 10 × 0.08 = 0.8   0.8 C8diglyceride 38 2 × (8 × 0.38) = 6.08 6.08/2 = 3.04 C10 diglyceride 7 2 ×(10 × 0.07) = 1.4 1.4/2 = 0.7 OIL ECN (normalized 8.3 to monoglycerides)

Expressed differently, ECN can be calculated as each chain length in thecomposition multiplied by its relative percentage in the oil:(8*0.85)+(10*0.15)=8.3.

The term “polysorbate” refers to a compound having the structure:

wherein w+x+y+z ranges from about 10 to about 50, and in particularembodiments, from about 10 to about 30, and wherein R is a C6-C18 fattyacid radical. Exemplary polysorbates within the scope of the presentdefinition include, but are not limited to, polysorbate 20, polysorbate40, polysorbate 60, polysorbate 65, and polysorbate 80.

The term “excipients,” as used herein, refers to non-API ingredientssuch as solubilizing agents, anti-oxidants, oils, lubricants,dissolution aids, terpenes, and others used in formulatingpharmaceutical products.

The phrase “therapeutically effective amount” refers to an amount of apharmaceutical composition or of a given steroid hormone suitable totreat a particular symptom, disorder, or disease.

As used herein, the phrase “substantially pure” means that an identifiedcomponent is at least about 90% pure by weight, in certain embodiments,at least about 95% pure by weight, and in still further embodiments, atleast about 98% pure by weight.

As used herein, the phrase “steroid hormone” refers to progesterone,17-hydroxyprogesterone, 5α-dihydroprogesterone, and estradiol.

As used herein, the term “d-limonene” refers to(4R)-1-methyl-4-(1-methylethenyl)-cyclohexene (CAS No. 5989-27-5), whichis also known by synonyms including(+)-4-isopropenyl-1-methylcyclohexene, (+)-p-mentha-1,8-diene, and(R)-(+)-Limonene.

As used herein, the phrase “reference product” refers to PROMETRIUM forprogesterone and ESTRACE tablets for estradiol, unless otherwisespecified.

Pharmaceutical Compositions

The pharmaceutical compositions disclosed herein are capable of fullysolubilizing steroid hormones, and in particular, progesterone andestradiol. Surprisingly, the pharmaceutical compositions in thisdisclosure provide a significantly better pharmacokinetic (“PK”) profilefor steroid hormones, and progesterone in particular, in a subject inneed thereof than currently marketed pharmaceutical compositions, suchas PROMETRIUM. The present pharmaceutical compositions achieve thisenhanced PK profile despite containing from about ⅙ to about ⅛ as muchprogesterone as a comparable volume of PROMETRIUM. PROMETRIUM, forexample, contains approximately 400 mg of progesterone per gram offormulation, while the pharmaceutical compositions provided in thisdisclosure contain, in certain embodiments, from about 10 to about 100mg progesterone per gram of pharmaceutical composition, and in certainembodiments, about 60 mg progesterone per gram of pharmaceuticalcomposition. Thus, and by way of example only, if a human subject wereadministered a 500 mg gel cap (a common gelcap size) of PROMETRIUM or agelcap containing 500 mg of a pharmaceutical compositions disclosedherein comprising about 6 weight percent progesterone, the PROMETRIUMdose would contain 200 mg of progesterone compared to only 30 mg ofprogesterone in the exemplary pharmaceutical composition. Thus, thehuman receiving the exemplary composition would receive significantlyless progesterone than the subject dosed with PROMETRIUM. Despite thediscrepancy in the amount of progesterone dosed, it has now beensurprisingly found, that the present compositions provide significantlyincreased bioavailability compared to PROMETRIUM. The enhancedbioavailability of progesterone or other steroid hormone in the presentcomposition allows for a significant reduction in the amountprogesterone, or other steroid hormone, that must be administered to asubject per dose to achieve the same or better results as PROMETRIUM.

Without wishing to be bound by any particular theory, it is believedthat, in certain embodiments, the described pharmaceutical compositionsform micelles upon administration that both protect the steroidhormone(s) from the digestive milieu and facilitate absorption of thesteroid hormone(s) across the gut mucosa and into the blood stream,which may facilitate the enhanced bioavailability. That said, in otherembodiments, and without wishing to be bound by any particular theory,the enhanced bioavailability observed in all of the present compositionsmay be due to the fully-solubilized nature of the progesterone presentin the compositions and the absence of suspended (insoluble)progesterone. Thus, in some embodiments, the pharmaceutical compositioncan be characterized as a fully-solubilized progesterone pharmaceuticalcomposition capable of forming micelles. Other embodiments, however, maycomprise fully-solubilized progesterone but may not form micelles. Instill other embodiments, the presence of both fully-solubilizedprogesterone and the formation of micelles together in the samepharmaceutical composition may result in an effect that further enhancesthe bioavailability of the progesterone above the bioavailability thatwould result if either only micelles were formed or onlyfully-solubilized progesterone were present.

Progesterone Compositions Capable of Forming Micelles

In certain embodiments, this disclosure provides a pharmaceuticalcomposition providing enhanced oral bioavailability of a steroidhormone, such as progesterone, wherein the pharmaceutical compositioncan comprise a steroid hormone, such as progesterone, a polysorbate, anda medium chain oil.

In certain embodiments, the medium chain oil in the pharmaceuticalcomposition can comprise at least about 50 weight percent of a mediumchain monoglyceride. In certain embodiments, the medium chainmonoglyceride and progesterone can be present at a weight ratio of about8:1 to about 15:1, about 9:1 to about 15:1, about 9:1 to about 14:1,about 9:1 to about 13:1, about 9:1 to about 12:1, about 9:1 to about11:1, or about 10:1. In particular embodiments, the medium chainmonoglyceride and progesterone can be present in a ratio of about 10:1.

In certain embodiments, the polysorbate can comprise from about 1 weightpercent to about 15 weight percent of the pharmaceutical composition andin particular embodiments, can be about 1 weight percent, about 2 weightpercent, about 3 weight percent, about 4 weight percent, about 5 weightpercent, about 6 weight percent, about 7 weight percent, about 8 weightpercent, about 9 weight percent, about 10 weight percent, about 11weight percent, about 12 weight percent, about 13 weight percent, about14 weight percent, or about 15 weight percent of the pharmaceuticalcomposition. In particular embodiments, the polysorbate can be about 5weight percent or about 7 weight percent of the pharmaceuticalcomposition.

In certain embodiments, the steroid hormone and the polysorbate presentin the pharmaceutical composition are present in a weight ratio of about1:2 to about 2:1.

In certain embodiments, the polysorbate can be selected from the groupconsisting of polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 65, and polysorbate 80. These polysorbates are commerciallyavailable and well known to those of skill in the art. In certainembodiments, the polysorbate can be polysorbate 80. In even moreparticular embodiments, the polysorbate 80 can comprise about 5 weightpercent or about 7 weight percent of the pharmaceutical composition.

In certain embodiments, the medium chain oil can comprise from about 50weight percent to about 90 weight percent of the pharmaceuticalcomposition. In particular embodiments, the medium chain oil cancomprise from about 60 weight percent to about 90 weight percent, fromabout 65 weight percent to about 90 weight percent, from about 70 weightpercent to about 90 weight percent, from about 75 weight percent toabout 90 weight percent, or from about 75 weight percent to about 85weight percent. In particular embodiments, the medium chain oil cancomprise about 80 weight percent or about 85 weight percent of thepharmaceutical composition.

In certain embodiments, the medium chain oil can comprise a singlemedium chain oil component. In other embodiments, the medium chain oilcan comprise a first medium chain oil component and a second mediumchain oil component. In still further embodiments, the medium chain oilcan comprise a first medium chain oil component, a second medium chainoil component, and a third medium chain oil component. In still furtherembodiments, the medium chain oil can comprise first, second, third andfourth; first, second, third, fourth, and fifth; or first, second,third, fourth, fifth, and sixth medium chain oil components.

In certain embodiments, the medium chain oil components themselves canbe multi-component oils. For example, certain medium chain oils comprisea mixture of mono and diglycerides or a mixture of mono-, di-, andtriglycerides, etc.

In particular embodiments, the medium chain oil can comprise a firstmedium chain oil component and a second medium chain oil component, withthe first medium chain oil component comprising from about 30 weightpercent to about 98 weight percent of the medium chain oil. In otherembodiments, the first medium chain oil component can comprise fromabout 40 weight percent to about 95 weight percent of the medium chainoil. In still further embodiments, the first medium chain oil componentcan comprise from about 50 weight percent to about 90 weight percent ofthe medium chain oil.

In certain embodiments, the medium chain oil can comprise at least about50 weight percent of a medium chain monoglyceride. In particularembodiments, the medium chain oil can comprise at least about at leastabout 55 weight percent of a medium chain monoglyceride, at least aboutat least about 60 weight percent of a medium chain monoglyceride, atleast about 65 weight percent of a medium chain monoglyceride, at leastabout 70 weight percent of a medium chain monoglyceride, at least about71 weight percent of a medium chain monoglyceride, at least about 72weight percent of a medium chain monoglyceride, at least about 73 weightpercent of a medium chain monoglyceride, at least about 74 weightpercent of a medium chain monoglyceride, at least about 75 weightpercent of a medium chain monoglyceride, at least about 76 weightpercent of a medium chain monoglyceride, at least about 77 weightpercent of a medium chain monoglyceride, at least about 78 weightpercent of a medium chain monoglyceride, at least about 79 weightpercent of a medium chain monoglyceride, at least about 80 weightpercent of a medium chain monoglyceride, at least about 81 weightpercent of a medium chain monoglyceride, at least about 82 weightpercent of a medium chain monoglyceride, at least about 83 weightpercent of a medium chain monoglyceride, at least about 84 weightpercent of a medium chain monoglyceride, at least about 85 weightpercent of a medium chain monoglyceride, at least about 86 weightpercent of a medium chain monoglyceride, at least about 87 weightpercent of a medium chain monoglyceride, at least about 88 weightpercent of a medium chain monoglyceride, at least about 89 weightpercent of a medium chain monoglyceride, or at least about 90 weightpercent of a medium chain monoglyceride. In certain embodiments, themedium chain oil can comprise at least about 85 weight percent of amedium chain monoglyceride and in an even further embodiment, the mediumchain oil can comprise at least about 90 weight percent of a mediumchain monoglyceride.

The medium chain monoglyceride can be, predominantly, a single mediumchain monoglyceride, such as glyceryl monocaproate, glycerylmonocaprylate, glyceryl monocaprate, glyceryl monolaurate, or glycerylmonomyristate. These monoglycerides are well known to those of ordinaryskill in the art and are available in various commercial embodiments,including from ABITEC Corp, a division of Associated British Food, PLC,as CAPMUL 708G, CAPMUL 808G, CAPMUL MCM C8, and CAPMUL MCM C10. Inparticular embodiments, the medium chain monoglyceride can be,predominantly, a single medium chain monoglyceride such as glycerylmonocaproate, glyceryl monocaprylate, or glyceryl monocaprate. Inspecific embodiments, the medium chain monoglyceride can be,predominantly, glyceryl monocaprylate, commercially available as CAPMUL708G.

In other embodiments, the medium chain monoglyceride can comprise amixture of medium chain monoglycerides, such as a combination of two ormore of glyceryl monocaproate, glyceryl monocaprylate, glycerylmonocaprate, glyceryl monolaurate, or glyceryl monomyristate. Inparticular embodiments, the mixture of medium chain monoglycerides canbe a mixture of glyceryl monocaprylate and glyceryl monocaprate. Inembodiments such as this, the glyceryl monocaprylate can comprise atleast about 80 weight percent, at least about 85 weight percent, atleast about 86 weight percent, at least about 87 weight percent, atleast about 88 weight percent, at least about 88 weight percent, atleast about 89 weight percent, or at least about 90 weight percent ofthe mixture of monoglycerides.

In certain embodiment, in addition to comprising a medium chainmonoglyceride, the medium chain oil can further comprise one or moremedium chain diglycerides. The one or more medium chain diglycerides canbe simple diglycerides, such as glyceryl dicaproate, glyceryldicaprylate, glyceryl dicaprate, glyceryl dilaurate, or glyceryldimyristate. Alternatively, the one or more medium chain diglyceridescan be mixed or complex diglycerides such as glycerylcaproate/caprylate, glyceryl caproate/caprate, glycerylcaproate/laurate, glyceryl caproate/myristate, glycerylcaprylate/caprate, glyceryl caprylate/laurate, glycerylcaprylate/myristate, glyceryl caprate/laurate, glycerylcaprate/myristate, or glyceryl laurate/myristate. In specificembodiments, the one or more medium chain diglycerides can be glycerylcaprylate/caprate. Exemplary commercially available medium chaindiglycerides include, but are not limited to, CAPMUL 471, CAPMUL MCM,CAPMUL MCM NF, CAPMUL MCM EP, and IMWITOR 742. The CAPMULs arecommercially available from ABITEC Corp.

The one or more medium chain diglycerides can comprise up to about 10weight percent of the medium chain oil or alternatively from about 5 toabout 10 weight percent of the pharmaceutical composition. In particularembodiments, the one or more medium chain diglycerides can compriseabout 5 weight percent, about 6 weight percent, about 7 weight percent,about 8 weight percent, about 9 weight percent, or about 10 weightpercent of the pharmaceutical composition. In specific embodiments, theone or more medium chain diglycerides can comprise about from about 8 toabout 9 weight percent of the pharmaceutical composition, such as about8 weight percent, about 8.1 weight percent, about 8.2 weight percent,about 8.3 weight percent, about 8.4 weight percent, about 8.5 weightpercent, about 8.6 weight percent, about 8.7 weight percent, about 8.8weight percent, about 8.9 weight percent, or about 9 weight percent ofthe pharmaceutical composition.

In certain embodiments, the one or more medium chain diglycerides can beglyceryl caprylate/caprate and the pharmaceutical composition cancomprise about 8 weight percent to about 9 weight percent of thiscomponent. A commercially available component suitable for use in thepharmaceutical composition is CAPMUL MCM NF.

Because of the manner in which they are prepared, medium chain oilsoften contain some amount of material that is greater in length thanC14. That said, this fraction is typically small and does not affect theoverall performance of a given medium chain oil. As such, and in certainembodiments, the amount of material greater than C14 in a given mediumchain oil comprises less than 20 weight percent, less than 15 weightpercent, less than 5 weight percent, less than 2.5 weight percent, lessthan 1 weight percent, less than 0.5 weight percent, or less than 0.1weight percent of a given medium chain oil.

Similarly, monoglycerides and diglycerides often contain di- andtriglyceride components in the case of a monoglyceride or mono- andtriglycerides in the case of diglycerides. The quantity of thesecomponents in a given mono- or diglyceride can vary, but is typicallyless than 20 weight percent, less than 15 weight percent, less than 5weight percent, less than 2.5 weight percent, less than 1 weightpercent, less than 0.5 weight percent, or less than 0.1 weight percentof the mono- or diglyceride. In all cases, the average ECN will be inthe range of 12-28 for diglycerides and 6-14 for monoglycerides.

In addition to the components noted above, in certain embodiments, thepharmaceutical composition can optionally further include apolyoxyethylene hydrogenated castor oil. In particular embodiments, thepolyoxyethylene hydrogenated castor oil can be referred to as a “PEG (orpolyoxyl) X Hydrogenated Castor Oil,” wherein X refers to the amount ofpegylation. In particular embodiments, X can be a number from 1 to 100and in certain embodiments, can be 7, 40, 40-45, or 60. Exemplarycommercially available PEG/polyoxyl X hydrogenated castor oils includeCREMOPHOR EL, CREMOPHOR RH40 (available commercially from BASF aspolyoxyl 40 hydrogenated castor oil (also known as KOLLIPHOR RH 40)),ETOCAS 40, CRODURET 7, CRODURET 40, CRODURET 50, CRODURET 60, andKOLLIPHOR HS 15. In particular embodiments, the polyoxyethylenehydrogenated castor oil can be polyoxyl 40 hydrogenated castor oil(KOLLIPHOR RH 40).

When present, the polyoxyethylene hydrogenated castor oil can comprisefrom about 1 to about 10 weight percent of the pharmaceuticalcomposition. In particular embodiments, the polyoxyethylene hydrogenatedcastor oil can comprise from about 2 to about 9 weight percent of thepharmaceutical composition, from about 3 to about 7 weight percent ofthe pharmaceutical composition, from about 4 to about 6 weight percentof the pharmaceutical composition, or about 4 to about 5 weight percentof the pharmaceutical composition. In particular embodiments, thepolyoxyethylene hydrogenated castor oil can comprise about 4 weightpercent of the pharmaceutical composition, about 4.1 weight percent ofthe pharmaceutical composition, about 4.2 weight percent of thepharmaceutical composition, about 4.3 weight percent of thepharmaceutical composition, about 4.4 weight percent of thepharmaceutical composition, about 4.5 weight percent of thepharmaceutical composition, about 4.6 weight percent of thepharmaceutical composition, about 4.7 weight percent of thepharmaceutical composition, about 4.8 weight percent of thepharmaceutical composition, or about 4.9 weight percent of thepharmaceutical composition.

In other embodiments, the pharmaceutical composition can optionallyinclude a d-α-tocopherol polyethylene glycol succinate (TPGS) derivativehaving the formula:

wherein n can range from 1 to about 100, and in particular embodiments,from about 1 to about 50 or about 1 to about 25. In particularembodiments, the D-α-Tocopherol polyethylene glycol succinate derivativecan be d-α-tocopherol polyethylene glycol 1000 succinate, also referredto as TPGS-1000 (n≈22).

The d-α-tocopherol polyethylene glycol succinate derivative, whenpresent, can comprise from about 0.1 weight percent to about 5 weightpercent of the pharmaceutical composition and in particular embodimentsabout 1 weight percent, about 1.5 weight percent, about 1.75 weightpercent, about 2 weight percent, about 2.1 weight percent, about 2.2weight percent, about 2.3 weight percent, about 2.4 weight percent,about 2.5 weight percent, about 2.75 weight percent, about 3 weightpercent, about 3.25 weight percent, about 3.5 weight percent, about 3.75weight percent, about 4 weight percent, about 4.25 weight percent, about4.5 weight percent, or about 4.75 weight percent of the pharmaceuticalcomposition. In certain embodiments, the d-α-tocopherol polyethyleneglycol succinate derivative can comprise about 2.3 weight percent of thepharmaceutical composition. In other embodiments, the pharmaceuticalcomposition can comprise TPGS-1000 at about 2.3 weight percent.

Generally speaking, and in certain embodiments, when the pharmaceuticalcomposition includes a d-α-tocopherol polyethylene glycol succinatederivative, the pharmaceutical composition does not include apolyoxyethylene hydrogenated castor oil. Similarly, and in certainembodiments, when the pharmaceutical composition includes apolyoxyethylene hydrogenated castor oil, the pharmaceutical compositiondoes not include a d-α-tocopherol polyethylene glycol succinatederivative.

As noted at the outset, the pharmaceutical compositions of the presentdisclosure are believed to form micelles after oral administration.Micelle formation can be observed by adding the pharmaceuticalcompositions described herein to water or other aqueous-based fluid suchas simulated gastric fluid (SGF). The size or size distribution of themicelles resulting from mixing the pharmaceutical compositions withwater or SGF can be measured using photon correlation spectroscopy. Incertain embodiments, the particles can have a size distribution rangingfrom about 1 nm to about 1400 nm in water, or from about 130 nm to about465 nm in water, or from about 100 nm to about 210 nm in water.

In certain embodiments, the micelles can have a zeta potential (mV)ranging from about −10 to about −30 mV. In certain embodiments, the zetapotential of the micelles can be about −10 mV, about −11 mV, about −12mV, about −13 mV, about −14 mV, about −15 mV, about −16 mV, about −17mV, about −18 mV, about −19 mV, about −20 mV, about −21 mV, about −22mV, about −23 mV, about −24 mV, about −25 mV, about −26 mV, about −27mV, about −28 mV, about −29 mV, or about −30 mV. In certain embodiments,the zeta potential can be about −16 to about −17 mV. In otherembodiments, the zeta potential can be about −18 to about −19 mV. Instill other embodiments, the zeta potential can be about −20 to about−21 mV.

Non-Micelle Forming Pharmaceutical Compositions

In another embodiment, the present disclosure provides non-micelleforming, fully-solubilized steroid hormone pharmaceutical compositions.These compositions comprise one or more steroid hormones, and inparticular embodiments, progesterone and a medium chain oil.

In certain embodiments, the medium chain oil in the pharmaceuticalcomposition can comprise at least about 50 weight percent of a mediumchain monoglyceride. In certain embodiments, the medium chainmonoglyceride and progesterone can be present at a weight ratio of about8:1 to about 15:1, about 9:1 to about 15:1, about 9:1 to about 15:1,about 10:1 to about 15:1, about 11:1 to about 15:1, about 12:1 to about15:1, about 13:1 to about 15:1, or about 14:1. In particularembodiments, the medium chain monoglyceride and progesterone can bepresent in a ratio of about 14:1.

In certain embodiments of the non-micelle forming pharmaceuticalcomposition, the medium chain oil can comprise from about 50 weightpercent to about 95 weight percent of the pharmaceutical composition. Inparticular embodiments, the medium chain oil can comprise from about 60weight percent to about 95 weight percent, from about 65 weight percentto about 95 weight percent, from about 70 weight percent to about 95weight percent, from about 75 weight percent to about 95 weight percent,or from about 85 weight percent to about 95 weight percent. Inparticular embodiments, the medium chain oil can comprise about 94weight percent of the non-micelle forming pharmaceutical composition.

In certain embodiments, the medium chain oil can comprise a singlemedium chain oil component. In other embodiments, the medium chain oilcan comprise a first medium chain oil component and a second mediumchain oil component. In still further embodiments, the medium chain oilcan comprise a first medium chain oil component, a second medium chainoil component, and a third medium chain oil component. In still furtherembodiments, the medium chain oil can comprise first, second, third andfourth; first, second, third, fourth, and fifth; or first, second,third, fourth, fifth, and sixth medium chain oil components.

In certain embodiments, the medium chain oil components themselves canbe multi-component oils. For example, certain medium chain oils comprisea mixture of mono and diglycerides or a mixture of mono-, di-, andtriglycerides, etc.

In particular embodiments, the medium chain oil can comprise a firstmedium chain oil component and a second medium chain oil component, withthe first medium chain oil component comprising from about 30 weightpercent to about 98 weight percent of the medium chain oil. In otherembodiments, the first medium chain oil component can comprise fromabout 40 weight percent to about 95 weight percent of the medium chainoil. In still further embodiments, the first medium chain oil componentcan comprise from about 50 weight percent to about 90 weight percent ofthe medium chain oil.

In certain embodiments, the medium chain oil can comprise at least about50 weight percent of a medium chain monoglyceride. In particularembodiments, the medium chain oil can comprise at least about at leastabout 55 weight percent of a medium chain monoglyceride, at least aboutat least about 60 weight percent of a medium chain monoglyceride, atleast about 65 weight percent of a medium chain monoglyceride, at leastabout 70 weight percent of a medium chain monoglyceride, at least about71 weight percent of a medium chain monoglyceride, at least about 72weight percent of a medium chain monoglyceride, at least about 73 weightpercent of a medium chain monoglyceride, at least about 74 weightpercent of a medium chain monoglyceride, at least about 75 weightpercent of a medium chain monoglyceride, at least about 76 weightpercent of a medium chain monoglyceride, at least about 77 weightpercent of a medium chain monoglyceride, at least about 78 weightpercent of a medium chain monoglyceride, at least about 79 weightpercent of a medium chain monoglyceride, at least about 80 weightpercent of a medium chain monoglyceride, at least about 81 weightpercent of a medium chain monoglyceride, at least about 82 weightpercent of a medium chain monoglyceride, at least about 83 weightpercent of a medium chain monoglyceride, at least about 84 weightpercent of a medium chain monoglyceride, at least about 85 weightpercent of a medium chain monoglyceride, at least about 86 weightpercent of a medium chain monoglyceride, at least about 87 weightpercent of a medium chain monoglyceride, at least about 88 weightpercent of a medium chain monoglyceride, at least about 89 weightpercent of a medium chain monoglyceride, at least about 90 weightpercent of a medium chain monoglyceride, or at least about 90 weightpercent of a medium chain monoglyceride. In certain embodiments, themedium chain oil can comprise at least about 90 weight percent of amedium chain monoglyceride.

The medium chain monoglyceride can be, predominantly, a single mediumchain monoglyceride, such as glyceryl monocaproate, glycerylmonocaprylate, glyceryl monocaprate, glyceryl monolaurate, or glycerylmonomyristate. These monoglycerides are well known to those of ordinaryskill in the art and are available in various commercial embodiments,including from ABITEC Corp, a division of Associated British Food, PLC,as CAPMUL 708G, CAPMUL 808G, CAPMUL MCM C8, and CAPMUL MCM C10. Inparticular embodiments, the medium chain monoglyceride can be,predominantly, a single medium chain monoglyceride such as glycerylmonocaproate, glyceryl monocaprylate, or glyceryl monocaprate. Inspecific embodiments, the medium chain monoglyceride can be,predominantly, glyceryl monocaprylate, commercially available as CAPMUL708G.

In other embodiments, the medium chain monoglyceride can comprise amixture of medium chain monoglycerides, such as a combination of two ormore of glyceryl monocaproate, glyceryl monocaprylate, glycerylmonocaprate, glyceryl monolaurate, or glyceryl monomyristate. Inparticular embodiments, the mixture of medium chain monoglycerides canbe a mixture of glyceryl monocaprylate and glyceryl monocaprate. Inembodiments such as this, the glyceryl monocaprylate can comprise atleast about 80 weight percent, at least about 85 weight percent, atleast about 86 weight percent, at least about 87 weight percent, atleast about 88 weight percent, at least about 88 weight percent, atleast about 89 weight percent, or at least about 90 weight percent ofthe mixture of monoglycerides.

In certain embodiment, in addition to comprising a medium chainmonoglyceride, the medium chain oil can further comprise one or moremedium chain diglycerides. The one or more medium chain diglycerides canbe simple diglycerides, such as glyceryl dicaproate, glyceryldicaprylate, glyceryl dicaprate, glyceryl dilaurate, or glyceryldimyristate. Alternatively, the one or more medium chain diglyceridescan be mixed or complex diglycerides such as glycerylcaproate/caprylate, glyceryl caproate/caprate, glycerylcaproate/laurate, glyceryl caproate/myristate, glycerylcaprylate/caprate, glyceryl caprylate/laurate, glycerylcaprylate/myristate, glyceryl caprate/laurate, glycerylcaprate/myristate, or glyceryl laurate/myristate. In specificembodiments, the one or more medium chain diglycerides can be glycerylcaprylate/caprate. Exemplary commercially available medium chaindiglycerides include, but are not limited to, CAPMUL 471, CAPMUL MCM,CAPMUL MCM NF, CAPMUL MCM EP, and IMWITOR 742. The CAPMULs arecommercially available from ABITEC Corp.

The one or more medium chain diglycerides can comprise up to about 10weight percent of the medium chain oil or alternatively from about 5 toabout 10 weight percent of the pharmaceutical composition. In particularembodiments, the one or more medium chain diglycerides can compriseabout 5 weight percent, about 6 weight percent, about 7 weight percent,about 8 weight percent, about 9 weight percent, or about 10 weightpercent of the pharmaceutical composition. In specific embodiments, theone or more medium chain diglycerides can comprise about from about 8 toabout 9 weight percent of the pharmaceutical composition, such as about8 weight percent, about 8.1 weight percent, about 8.2 weight percent,about 8.3 weight percent, about 8.4 weight percent, about 8.5 weightpercent, about 8.6 weight percent, about 8.7 weight percent, about 8.8weight percent, about 8.9 weight percent, or about 9 weight percent ofthe pharmaceutical composition.

In certain embodiments, the one or more medium chain diglycerides can beglyceryl caprylate/caprate and the pharmaceutical composition cancomprise about 8 weight percent to about 10 weight percent of thiscomponent. A commercially available component suitable for use in thepharmaceutical composition is CAPMUL MCM NF.

Excluded Ingredients

In certain embodiments, the pharmaceutical compositions described inthis disclosure are completely or substantially free of animal oils,vegetable oils, fractionated vegetable oils, all Omega-3 free fattyacids, all Omega-3 fatty acid esters, EPA fatty acid esters, and DHAfatty acid esters. Exemplary excluded animal oils include, but are notlimited to, fish liver oils, shark oil, and mink oil. Exemplary excludedfractionated vegetable oils include, but are not limited to,fractionated coconut oils. Exemplary excluded vegetable oils include soybean oil, safflower seed oil, corn oil, olive oil, cottonseed oil,arachis oil, sunflower seed oil, coconut oil, palm oil, and rape seedoil. Exemplary excluded Omega-3 free fatty acids and Omega-3 fatty acidesters, include, for example, hexadecatrienoic acid, α-linolenic acid,stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid,heneicosapentaenoic acid, docosapentenoic acid, docosahexaenoic acid,tetracosapentenoic acid, tetracosahexaenoic acid, combinations thereof,and esters thereof.

Steroid Hormones

In certain embodiments, the pharmaceutical compositions in thisdisclosure can comprise from about 0.025 weight percent to about 15weight percent of a steroid hormone. In certain embodiments, thepharmaceutical composition can comprise from about 0.025 weight percentsteroid hormone to about 10 weight percent steroid hormone, from about 1to about 10 weight percent steroid hormone, about 1 to about 9 weightpercent steroid hormone, from about 1 to about 8 weight percent steroidhormone, from about 1 to about 7 weight percent steroid hormone, fromabout 2 to about 7 weight percent steroid hormone, from about 3 to about7 weight percent steroid hormone, from about 4 to about 7 weight percentsteroid hormone, from about 5 to about 7 weight percent steroid hormone,or about 6 weight percent steroid hormone. In certain embodiments, thepharmaceutical compositions of this disclosure can comprise about 6weight percent steroid hormone, and in even still other embodiments,about 6 weight percent progesterone. In further embodiments,progesterone can be the sole active ingredient in the pharmaceuticalcomposition.

The steroid hormone, and in particular embodiments, progesterone, can bepartially solubilized (i.e., less than about 80% solubilized),solubilized, or fully solubilized, depending upon the specificcomponents of the composition. In typical embodiments, the steroidhormone is at least solubilized and in certain embodiments, fullysolubilized in the pharmaceutical composition. In some embodiments, thepharmaceutical composition is saturated such that additional steroidhormone will not dissolve. In some embodiments, the pharmaceuticalcomposition contains both solubilized and suspended (insoluble) steroidhormone. That said, and more typically, the steroid hormone is at leastabout 80%, at least about 85%, at least about 90%, at least about 95%,at least about 99%, or 100% solubilized in the pharmaceuticalcomposition at a given concentration. In certain embodiments, thesteroid hormone, and in particular progesterone, is fully solubilized,i.e., at least about 95 percent solubilized, at least about 98%solubilized, or at least about 99% solubilized as measured according tothe methodology described below. However, in other embodiments, theprogesterone can be solubilized or only partially solubilized.

The solubility of a given steroid hormone can be measured using standardtechniques by weighing a piece of filter paper, placing the weighedfilter paper in a buchner funnel (porcelain or glass with a glass frit),and drawing a known quantity of pharmaceutical composition through thefilter paper using vacuum (such as with a side-arm flask fitted with aneoprene collar). After drying for an appropriate period of time (eitherat room temperature or at elevated temperature), the filter paper isreweighed. The amount of steroid hormone on the filter paper iscalculated and the amount or percentage of solubilized and insolublesteroid hormone is calculated.

In certain embodiments, the steroid hormone is progesterone and inparticular embodiments, the progesterone can comprise about 6 weightpercent of the pharmaceutical composition. In some embodiments,progesterone is the sole active ingredient in the pharmaceuticalcomposition.

In certain embodiments, the steroid hormone can be a combination ofprogesterone and estradiol. In certain embodiments, the steroid hormoneis a progestogen, including, but not limited to bio-identicalprogesterone or progesterone analogs. In certain embodiments the steroidhormone is an estrogen, including estradiol, estrone, estriol, orestrogen analog.

Although the steroid hormone used to formulate the pharmaceuticalcomposition can have any particle size, in certain embodiments, thesteroid hormone can have an average particle size of less than about 100microns. In certain embodiments, the steroid hormone can be micronized.Without wishing to be bound by any particular theory, it is believedthat steroid hormones having a smaller average particle size will bemore soluble in the pharmaceutical composition.

Terpenes

All of the pharmaceutical compositions described in this disclosure canoptionally include a terpene. Terpenes are the primary constituents ofthe essential oils of many types of plants and flowers and are typicallyformed directly from one or more isoprene (C₅H₈) units. Terpenes can benaturally occurring or prepared synthetically. Terpenes can be obtainedfrom their natural source, for example, isolated from a natural oil suchas citrus oil or orange oil, and optionally purified to be substantiallypure, or synthesized chemically.

In certain embodiments, the terpene can be a terpenoid. Examples ofterpenes are provided, for example, in Dev et al., “CRC Handbook ofTerpenoids: Acyclic, Monocyclic, Bicyclic, Tricyclic, and TetracyclicTerpenoids” (1989) CRC Press Inc.; Hanson, J. R., Annu. Rep. Prog.Chem., Sect. B: Org. Chem., (1985) 82, 353-375; and Degenhardt et al.,Phytochemistry (2009) 70:1621-1637. Each of these references is herebyincorporated by reference in its entirety.

The optional terpene can be linear or cyclic (including aromatic). Acyclic terpene can be a monocyclic terpene or a bicyclic terpene. In aparticular embodiment, the cyclic terpene can be a monocyclic terpene.In certain embodiments, the cyclic terpene can be non-aromatic. Examplesof cyclic terpenes include, without limitation, limonene (as d-limonene,l-limonene, or a mixture thereof), phellandrene (alpha or beta),camphor, menthol, menthene, carvone, terpinene (alpha, beta, or gamma),terpineol (alpha, beta, or gamma), alpha-ionone, thujone, andderivatives thereof. In certain embodiments, the cyclic terpene islimonene, menthene, menthol, phellandrene, terpinene, or terpineol. Insome embodiments, the optional terpene can be d-limonene.

In certain embodiments, when the terpene is present, the terpene cancomprise from about 0.5 weight percent to about 10 weight percent of thepharmaceutical composition; from about 1 weight percent to about 10weight percent of the pharmaceutical composition; from about 2 weightpercent to about 9 weight percent of the pharmaceutical composition;from about 3 weight percent to about 8 weight percent of thepharmaceutical composition; from about 4 weight percent to about 8weight percent of the pharmaceutical composition; from about 5 weightpercent to about 7 weight percent of the pharmaceutical composition, orabout 6 weight percent of the pharmaceutical composition.

In certain embodiments, the optional terpene is d-limonene and ispresent in any of the amounts noted above. In other embodiments, theoptional terpene is d-limonene and is present at about 6 weight percentof the pharmaceutical composition.

Antioxidants

In certain embodiments, the pharmaceutical compositions can furtherinclude an antioxidant such as α-tocopherol acetate, acetone sodiumbisulfite, acetylcysteine, ascorbic acid, ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), cysteine, cysteinehydrochloride, α-tocopherol, dithiothreitol, monothioglycerol,nordihydroguaiaretic acid, propyl gallate, sodium bisulfite, sodiumformaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodiumthiosulfate, thiourea, tocopherol, or any combination thereof. Inparticular embodiments, the antioxidant is BHT.

The antioxidant can be included in an amount appropriate to inhibitoxidation of any, some, or all of the components of the pharmaceuticalcomposition for a desired period of time. For example, the antioxidantcan inhibit oxidation of any of the steroid hormone(s) present in thepharmaceutical composition, the medium chain oil, the polysorbate, thepolyoxyethylene hydrogenated castor oil, the D-α-Tocopherol polyethyleneglycol succinate derivative, or the terpene to the extent thesecomponents are present in the composition. In certain embodiments, theantioxidant is present to inhibit the oxidation of the terpene, which incertain embodiments, can be d-limonene. In certain embodiments, the BHTis present in the pharmaceutical composition at from about 0.01 to about0.1 weight percent. In other embodiments, the BHT is present at about0.03 weight percent.

Methods of Treating Hormone Deficiencies

In certain embodiments, this disclosure provides methods for treatingone or more conditions associated with hormone deficiency in a subject.The methods comprise orally administering to a subject in need thereofan effective amount of the pharmaceutical composition described herein.

In some embodiments, the condition being treated can be a progesteronedeficiency. In some embodiments, the condition can be endometrialhyperplasia, secondary amenorrhea, hot flashes, night sweats, sleepdisturbances, mood changes, or osteoporosis. In some embodiments, thepharmaceutical composition disclosed herein can be used to counteractside effects of estradiol in subjects receiving estradiol therapy.

In some embodiments, the condition being treated can be an estrogendeficiency. In some embodiments, the condition can be hot flashes, nightsweats, sleep disturbances, mood changes, vulvovaginal atrophy, orosteoporosis.

In certain embodiments, the pharmaceutical composition can beadministered to a subject in need thereof, such that the subjectreceives steroid hormone, and in particular embodiments, progesterone,in an amount ranging from about 0.1 mg to about 1 g; about 1 mg to about600 mg; or about 10 mg to about 500 mg. In certain specific embodiments,the steroid hormone is progesterone.

In other embodiments, the progesterone can be administered to a subjectin need thereof, and in particular a human, using the pharmaceuticalcompositions in this disclosure so that the subject/human in needthereof receives an amount of progesterone ranging from about 10 mg toabout 500 mg, and in certain embodiments, about 10 mg, about 15 mg,about 20 mg, about 25 mg, 30 mg, about 35 mg, about 40 mg, about 45 mg,about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg,about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg,about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg,about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg,about 500 mg, or any range encompassing any of the noted values.

In particular embodiments, the amount of progesterone administered perdose using the pharmaceutical composition in this disclosure to a humanin need thereof, can range from about 10 mg to about 50 mg or from about15 mg to about 45 mg. In certain embodiments, the amount of progesteroneadministered to a subject in need thereof using the pharmaceuticalcomposition of this disclosure can be about 15 mg, about 16 mg, about 17mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg,about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about36 mg, about 37, about 38 mg, about 39 mg, or about 40 mg progesterone.In particular embodiments, a human in need thereof can receive eitherabout 20 mg progesterone per dose or about 36 mg progesterone per dosewhen the pharmaceutical composition is administered.

To receive the desired amount of progesterone per dose, the human inneed thereof can, in certain embodiments, be administered from about 300mg to about 2000 mg of the pharmaceutical composition, from about 350 mgto about 1700 mg of the pharmaceutical composition, from about 400 mg toabout 1400 mg of the pharmaceutical composition, from about 450 mg toabout 1100 mg of the pharmaceutical composition, from about 500 mg toabout 800 mg of the pharmaceutical composition, from about 550 mg toabout 750 mg of the pharmaceutical composition, from about 575 mg toabout 625 mg of the pharmaceutical composition, or about 600 mg of thepharmaceutical formulation. In other embodiments, the human in needthereof can be administered about 300 to about 350 mg of thepharmaceutical composition. In other embodiments, the human in needthereof can be administered about 350 to about 400 mg of thepharmaceutical composition. In other embodiments, the human in needthereof can be administered about 400 to about 450 mg of thepharmaceutical composition. In other embodiments, the human in needthereof can be administered about 450 to about 500 mg of thepharmaceutical composition. In other embodiments, the human in needthereof can be administered about 500 to about 550 mg of thepharmaceutical composition. In other embodiments, the human in needthereof can be administered about 550 to about 600 mg of thepharmaceutical composition. In other embodiments, the human in needthereof can be administered about 600 to about 650 mg of thepharmaceutical composition.

In embodiments wherein the amount of progesterone in the composition isabout 6 weight percent of the composition and wherein the amount ofprogesterone to be administered to the human in need thereof is about 20mg, the amount of the pharmaceutical formulation that can beadministered to the human can be about 333 mg.

In embodiments wherein the amount of progesterone in the composition isabout 6 weight percent of the composition and wherein the amount ofprogesterone to be administered to the human in need thereof is about 36mg, the amount of the pharmaceutical formulation that can beadministered to the human can be about 600 mg.

These dosages reflect the surprisingly enhanced bioavailability ofprogesterone provided by the present pharmaceutical compositions. Thesecompositions provide the opportunity to reduce the amount ofprogesterone administered to a human in need thereof relative tocurrently marketed products such as PROMETRIUM. As discussed elsewhereherein, the PK parameters observed when the present pharmaceuticalcompositions are dosed are highly surprising in view of the known PKparameters associated with PROMETRIUM.

In certain embodiments, the pharmaceutical compositions can beadministered to a human in need thereof in the amounts described abovefor the treatment of a disease or conditions treatable withprogesterone. Such diseases and conditions include, but are not limitedto, endometrial hyperplasia; secondary amenorrhea; prevention of pretermbirth; and osteoporosis.

In certain embodiments, a human can be administered from about 300 mg toabout 650 mg of a pharmaceutical compositions described herein to treatendometrial hyperplasia.

In other embodiments, a human can be administered from about 300 mg toabout 1000 mg of a pharmaceutical compositions described herein to treatsecondary amenorrhea.

In other embodiments, a human can be administered from about 300 mg toabout 650 mg of a pharmaceutical compositions described herein to treatpreterm birth.

In other embodiments, a human can be administered from about 300 mg toabout 650 mg of a pharmaceutical compositions described herein to treatosteoporosis.

In each of the above described embodiments, a human can be administeredabout a dose of about 333 mg or about 600 mg of the pharmaceuticalcomposition, such that the human receives about 20 mg or about 36 mg ofprogesterone per dose of the pharmaceutical composition.

In certain embodiments, the pharmaceutical composition can beadministered once daily within in any of the above noted amounts untilthe disease or condition is treated.

In further embodiments, about 333 mg of the pharmaceutical compositioncan be administered once daily to treat the disease or condition.

In still another embodiments, about 600 mg of the pharmaceuticalcomposition can be administered once daily to treat the disease orcondition.

In certain embodiments, the amount of pharmaceutical compositionadministered to a given human subject can be an amount that renders thepharmaceutical composition bioequivalent to PROMETRIUM.

In certain embodiments, the amount of the pharmaceutical compositionthat is bioequivalent to PROMETRIUM can be from about 300 to about 350mg of the pharmaceutical composition. In certain embodiments, thepharmaceutical composition can comprise about 6 weight percentprogesterone. And in still further embodiments, the amount ofprogesterone administered to the human subject using the presentpharmaceutical compositions to achieve bioequivalence to PROMETRIUM canbe about 20 mg progesterone.

In certain embodiments, the steroid hormone is estradiol. In someembodiments, the pharmaceutical composition can be administered suchthat a subject in need thereof receives an amount of estradiol in therange of about 0.01 mg to about 2 mg, and in certain embodiments, about2 mg, about 1 mg, about 0.75 mg, about 0.5 mg, about 0.25 mg, about 0.1mg, about 0.075 mg, about 0.050 mg, about 0.025 mg, about 0.01 mg, orany range encompassing any of the noted values.

In certain embodiments, the steroid hormone is a combination ofprogesterone and estradiol, with dosages as described in the precedingparagraphs.

Although the pharmacokinetic profiles of many progesterone formulationscan be affected by whether or not the formulation is taken with food, ithas been surprisingly discovered that, in some embodiments, the presentpharmaceutical compositions can deliver progesterone consistently bothin the presence and absence of food. That is, and surprisingly, in someembodiments, the present pharmaceutical compositions do not show a foodeffect. This is an extremely beneficial property of certain embodimentsof the disclosed pharmaceutical compositions as it allows for lessrestrictive dosing and increases the likelihood of patient compliancewith a given dosing regimen. Lack of a food effect may further reduceboth inter- and intra-patient variability when the pharmaceuticalcompositions of the present disclosure are dosed.

Pharmacokinetics and Metabolites

The disclosed pharmaceutical compositions can provide enhancedpharmacokinetics versus the currently marketed drug PROMETRIUM. Forexample, in certain embodiments, the pharmaceutical composition can havean AUC_(0-t) that is at least about 1.1, at least about 1.2, at leastabout 1.3, at least about 1.4, at least about 1.5, at least about 1.6,at least about 1.7, at least about 1.8, at least about 1.9, or at leastabout 2 times greater than PROMETRIUM when the pharmaceuticalcompositions are dosed in the fasting state. That is, the pharmaceuticalcompositions can have AUCs that are at least about 110 percent, at leastabout 120 percent, at least about 130 percent, at least about 140percent, at least about 150 percent, at least about 160 percent, atleast about 170 percent, at least about 180 percent, at least about 190percent, or at least about 200 percent the AUC of PROMETRIUM when thepharmaceutical compositions are dosed in the fasting state.

Similarly, in certain embodiments, the pharmaceutical composition canhave a C_(max) that is at least about 1.1, at least about 1.2, at leastabout 1.3, at least about 1.4, at least about 1.5, at least about 1.6,at least about 1.7, at least about 1.8, at least about 1.9, at leastabout 2, at least about 2.2, at least about 2.4, at least about 2.6, atleast about 2.8, or at least about 3 times greater than PROMETRIUM whenthe pharmaceutical compositions are dosed in the fasting state.

In certain embodiments, the pharmaceutical composition can have at_(max) that is at least about 3, at least about 4, at least about 5, atleast about 6, at least about 7, at least about 8, at least about 9, atleast about 10, at least about 11, at least about 12, at least about 13,at least about 14, at least about 15, at least about 16, or at leastabout 17 times shorter than PROMETRIUM when the pharmaceuticalcompositions are dosed in the fasting state. That is, and in certainembodiments, the pharmaceutical compositions disclosed herein reachtheir C_(max) considerably earlier than PROMETRIUM.

Methods for Preparing the Pharmaceutical Compositions

In certain embodiments, the compositions described herein can beprepared according to the following general procedure. In certainembodiments, and in a first step, the steroid hormone, and in particularembodiments, progesterone, can be solubilized in the medium chain oil bymixing the steroid hormone with the medium chain oil under mild heating,i.e. from about 35° C. to about 60° C., and in certain embodiments atabout 40° C. The mixture can be mixed for an amount of time sufficientto solubilize and uniformly distribute the steroid hormone in the mediumchain oil. Typically, the solubilization can be performed in anappropriate vessel, such as optionally temperature-controlled jacketedstainless steel vessel of the type typically found in medium and largescale formulation manufacturing facilities.

The medium chain oil can have properties described elsewhere herein andcan be added in the amounts specified elsewhere herein. In particularembodiments, the medium chain oil can comprise a mixture of a mediumchain monoglyceride and a medium chain diglyceride. In otherembodiments, however, the medium chain oil can comprise a medium chainmonoglyceride or a medium chain diglyceride.

As discussed elsewhere herein, the medium chain monoglyceride can be,predominantly, a single medium chain monoglyceride, such as glycerylmonocaproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonolaurate, or glyceryl monomyristate. These monoglycerides are wellknown to those of ordinary skill in the art and are available in variouscommercial embodiments, including from ABITEC Corp, a division ofAssociated British Food, PLC, as CAPMUL 708G, CAPMUL 808G, CAPMUL MCMC8, and CAPMUL MCM C10. In particular embodiments, the medium chainmonoglyceride can be, predominantly, a single medium chain monoglyceridesuch as glyceryl monocaproate, glyceryl monocaprylate, or glycerylmonocaprate. In specific embodiments, the medium chain monoglyceride canbe, predominantly, glyceryl monocaprylate, commercially available asCAPMUL 708G.

Similarly, and also discussed previously, the one or more medium chaindiglycerides can be simple diglycerides, such as glyceryl dicaproate,glyceryl dicaprylate, glyceryl dicaprate, glyceryl dilaurate, orglyceryl dimyristate. Alternatively, the one or more medium chaindiglycerides can be mixed or complex diglycerides such as glycerylcaproate/caprylate, glyceryl caproate/caprate, glycerylcaproate/laurate, glyceryl caproate/myristate, glycerylcaprylate/caprate, glyceryl caprylate/laurate, glycerylcaprylate/myristate, glyceryl caprate/laurate, glycerylcaprate/myristate, or glyceryl laurate/myristate. In specificembodiments, the one or more medium chain diglycerides can be glycerylcaprylate/caprate. Exemplary commercially available medium chaindiglycerides include, but are not limited to, CAPMUL 471, CAPMUL MCM,CAPMUL MCM NF, CAPMUL MCM EP, and IMWITOR 742. The CAPMULs arecommercially available from ABITEC Corp.

In certain embodiments, the one or more medium chain diglycerides can beglyceryl caprylate/caprate. A commercially available version of thiscomponent suitable for use in the pharmaceutical composition is CAPMULMCM NF.

Once the steroid hormone has sufficiently dissolved in the medium chainoil, additional components which can be included in a given compositionas specified elsewhere herein, can be added. For example, in certainembodiments, a polysorbate can be added to the medium chain oil/steroidhormone mixture in the amounts specified elsewhere herein. In certainembodiments, the polysorbate can be selected from the group consistingof polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, andpolysorbate 80. In certain embodiments, the polysorbate can bepolysorbate 80.

In certain embodiments, and in addition to the polysorbate, ad-α-tocopherol polyethylene glycol succinate (TPGS) derivative and anantioxidant can be added to the medium chain oil/steroid hormonemixture. Each of the d-α-tocopherol polyethylene glycol succinate (TPGS)derivative and an antioxidant can be added in the amounts and specificembodiments discussed elsewhere herein.

In other embodiments, in addition to the polysorbate, a PEG Xhydrogenated castor oil and an antioxidant can also be added to themedium chain oil/steroid hormone mixture. Each of the PEG X hydrogenatedcastor oil and an antioxidant can be added in the amounts and specificembodiments discussed elsewhere herein.

In each of the above noted embodiments, addition of the antioxidant canbe omitted.

Typically, and when added to a given composition, the various additionalcomponents are added with mixing and under mild heating to ensurehomogenous distribution of the various components in the composition.When present, each of the antioxidant, the polysorbate, thed-α-tocopherol polyethylene glycol succinate (TPGS) derivative, and thePEG X hydrogenated castor oil, can be added in the amounts andembodiments disclosed elsewhere herein.

Once the addition of all of the necessary or desired components iscomplete, the composition can be stirred until it reaches roomtemperature. Once at room temperature, and when desired, a terpene, suchas d-limonene, can be added to the composition in any of the amountsspecified elsewhere herein.

The resulting composition, after an optional deaeration process, canthen be used as the fill material in the encapsulation process disclosedelsewhere herein.

In another embodiment, the compositions described herein may be preparedby mixing the desired components, exclusive of the optional terpene, atroom temperature and subsequently warming the resulting mixture to fromabout 35° C. to about 60° C., and in certain embodiments to about 40° C.to affect dissolution of the steroid hormone. Following a sufficientamount of stirring to ensure the desired level of dissolution andhomogenous distribution of the various components in the composition,the mixture can be cooled to room temperature. After cooling, and as inthe alternative embodiment discussed above, a terpene, such asd-limonene, can be added to the composition in any of the amountsspecified elsewhere herein.

The resulting composition, after an optional deaeration process, canthen be used as the fill material in the encapsulation process discussedbelow.

Encapsulation

Although the pharmaceutical composition can be dosed as a liquid, incertain embodiments, the pharmaceutical composition can be encapsulatedin a gelatin capsule, or other similar encapsulated dosage form known tothose of skill in the art. The gelatin capsule can be a soft gelatincapsule or a hard gelatin capsule. The hard gelatin capsule can be atwo-piece, standard gelatin capsule which typically includes a firstcapsule portion (i.e., half or bottom) and a second capsule portion(i.e., the other half or top). The soft gelatin capsule can be atwo-piece capsule wherein two portions are sealed together or aone-piece, hermetically sealed capsule.

In certain embodiments, the soft gelatin capsule can be a one-piece,hermetically sealed gelatin based capsule which can be made bytechniques known to those skilled in the art. In certain embodiments,the gelatin used to form the soft gelatin capsule can include water,gelatin, and a plasticizer to control the softness and flexibility ofthe capsule. Other additives for use in the gelatin suitable forpreparing the soft gelatin capsule, include but are not limited to,flavorants, colorants, and opacifiers.

Soft gelatin capsules can be produced in a known manner, including witha rotary die process in which a molten mass of a gelatin containing theappropriate or necessary additives, is fed from a reservoir onto drumsto form two spaced sheets or ribbons of gelatin in a semi-molten state.These ribbons are fed around rollers and brought together at convergentangle into the nip of a pair of roller dies that include opposed diecavities. A liquid fill formulation, such as the pharmaceuticalcomposition of this disclosure, can then be fed into the wedge-shapedjoinder of the ribbons. The gelatin ribbons are continuously conveyedbetween the dies, with portions of the fill formulation being trappedbetween the sheets inside the die cavities. The sheets are then pressedtogether, and severed around each die so that opposed edges of the sheetflow together to form a continuous gelatin sheath around the entrappedliquid pharmaceutical composition. The part of the gelatin sheet that issevered from the segments forming the capsules can then be collected forrecycling or can be discarded. The resulting soft capsules can then bedried and packaged.

Various gelatin compositions known in the prior art can be used toencapsulate the pharmaceutical composition of this disclosure. Forexample, suitable gelatin capsules can be prepared from a gelatinmixture comprising from about 30% w/w to about 85% w/w gelatin and incertain embodiments, about 30% w/w to about 50% w/w; about 15% w/w toabout 40% w/w of one or more plasticizer; and from 25% w/w to about 50%w/w of water. In certain embodiments, the gelatin will have a bloom inthe rage of about 150 to about 275, and can be Type A or B gelatins or amixture thereof.

Examples of suitable Type A gelatin include without limitation acid bonegelatin. Examples of suitable Type B gelatin include without limitationlime bone gelatin.

Suitable gelatin plasticizers are well known to those of ordinary skillin the art and include, but are not limited to, polyhydric alcohols suchas sorbitol, glycerin, mannitol, xylitol, maltitol, and sorbitan;dialkylphthalates; lower alkyl citrates wherein the lower alkyl has 1-6carbon atoms; glycols and polyglycols including polyethylene glycolswith a molecular weight range of about 200 to about 2,000,methoxyl-propylene-glycol, and 1,2-propylene glycol; esters ofpolyhydroxy-alcohols such as mono-, di-, and tri-acetates of glycerol;ricinoleic acid and esters thereof; and mixtures of the above. Thegelatin pharmaceutical composition can also contain other ingredientsincluding, but not limited to, taste modifiers, coloring agents,opacifiers, and moisture retaining agents.

Additional Non-Limiting Embodiments

Additional non-limiting embodiments of the pharmaceutical compositionsand methods disclosed herein are described below:

-   -   (A) A pharmaceutical composition for providing enhanced oral        bioavailability of progesterone, the pharmaceutical composition        comprising: progesterone, a polysorbate, and a medium chain oil,        wherein the medium chain oil comprises at least about 50 weight        percent of a predominantly medium chain monoglyceride; and the        progesterone is fully solubilized.    -   (B) The pharmaceutical composition of embodiment (A), wherein        the medium chain oil comprises at least about 60 weight percent        of a predominantly medium chain monoglyceride.    -   (C) The pharmaceutical composition of embodiment (A), wherein        the medium chain oil comprises at least about 70 weight percent        of the predominantly medium chain monoglyceride.    -   (D) The pharmaceutical composition of embodiment (A), wherein        the medium chain oil comprises at least about 80 weight percent        of the predominantly medium chain monoglyceride.    -   (E) The pharmaceutical composition of embodiment (A), wherein        the medium chain oil comprises at least about 90 weight percent        of the predominantly medium chain monoglyceride.    -   (F) The pharmaceutical composition of embodiment (E), wherein        the polysorbate is selected from the group consisting of        polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65,        and polysorbate 80.    -   (G) The pharmaceutical composition of embodiment (A), wherein        the pharmaceutical composition provides an oral bioavailability        of at least about 150 percent as measured by an increase in AUC        when compared to a reference product.    -   (H) The pharmaceutical composition of embodiment (A), further        comprising a polyoxyethylene hydrogenated castor oil.    -   (I) The pharmaceutical composition of embodiment (A), further        comprising a D-α-Tocopherol polyethylene glycol succinate        derivative.    -   (J) The pharmaceutical composition of embodiment (A), further        comprising a terpene.    -   (K) The pharmaceutical composition of embodiment (A), wherein        the predominantly medium chain monoglyceride and the        progesterone can be present at a weight ratio of about 10:1 to        about 15:1.    -   (L) The pharmaceutical composition of embodiment (K), wherein        the predominantly medium chain monoglyceride comprises at least        about 60 weight percent of the medium chain oil.    -   (M) The pharmaceutical composition of embodiment (K), wherein        the predominantly medium chain monoglyceride comprises at least        about 70 weight percent of the predominantly medium chain oil.    -   (N) The pharmaceutical composition of embodiment (K), wherein        the predominantly medium chain monoglyceride comprises at least        about 80 weight percent of the medium chain oil.    -   (O) The pharmaceutical composition of embodiment (A), wherein        the predominantly medium chain monoglyceride comprises at least        about 90 weight percent of the medium chain oil.    -   (P) The pharmaceutical composition of embodiment (0), wherein        the polysorbate is selected from the group consisting of        polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65,        and polysorbate 80.    -   (Q) The pharmaceutical composition of embodiment (K), wherein        the pharmaceutical composition provides an oral bioavailability        of at least about 150 percent as measured by an increase in AUC        when compared to a reference product.    -   (R) The pharmaceutical composition of embodiment (K), further        comprising a polyoxyethylene hydrogenated castor oil.    -   (S) The pharmaceutical composition of embodiment (K), further        comprising a D-α-Tocopherol polyethylene glycol succinate        derivative.    -   (T) The pharmaceutical composition of embodiment (A), further        comprising a terpene.    -   (U) An oral, fully-solubilized progesterone pharmaceutical        composition comprising: progesterone and a polysorbate in a        weight ratio of from about 1:2 to about 2:1; and a medium chain        oil comprising a mixture of medium chain mono- and diglycerides,        the medium chain oil not containing more than about 10 weight        percent triglycerides.    -   (V) The pharmaceutical composition of embodiment (U), wherein        the polysorbate is selected from the group consisting of        polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65,        and polysorbate 80.    -   (W) The pharmaceutical composition of embodiment (U), wherein        the pharmaceutical composition provides an oral bioavailability        of at least about 150 percent as measured by an increase in AUC        when compared to a reference product.    -   (X) The pharmaceutical composition of embodiment (U), further        comprising a polyoxyethylene hydrogenated castor oil.    -   (Y) The pharmaceutical composition of embodiment (U), further        comprising a D-α-Tocopherol polyethylene glycol succinate        derivative.    -   (Z) The pharmaceutical composition of embodiment (U), further        comprising a terpene.    -   (AA) The pharmaceutical composition of any of embodiments (A)        through (T), wherein the predominantly medium chain        monoglyceride is glyceryl monocaproate, glyceryl monocaprylate,        glyceryl monocaprate, glyceryl monolaurate, or glyceryl        monomyristate.    -   (BB) The pharmaceutical composition of embodiment (AA), wherein        the medium chain monoglyceride is glyceryl monocaprylate.    -   (CC) The pharmaceutical composition of embodiment (BB), wherein        the glyceryl monocaprylate comprises at least about 85 weight        percent of the medium chain oil.    -   (DD) The pharmaceutical composition of embodiment (H), wherein        the polyoxyethylene hydrogenated castor oil is a polyoxyl X        hydrogenated castor oil and X is an integer from 1 to 100.    -   (EE) The pharmaceutical composition of embodiment (DD), wherein        the polyoxyethylene hydrogenated castor oil is polyoxyl 40        hydrogenated castor oil.    -   (FF) The pharmaceutical composition of embodiment (EE), wherein        the polyoxyl 40 hydrogenated castor oil comprises from about 1        to about 10 weight percent of the pharmaceutical composition.    -   (GG) The pharmaceutical composition of embodiment (FF), wherein        the polyoxyl 40 hydrogenated castor oil comprises about 4 weight        percent to about 5 weight percent of the pharmaceutical        composition.    -   (HH) The pharmaceutical composition of any of embodiments (A)        through (U), wherein the medium chain oil further comprises a        diglyceride.    -   (II) The pharmaceutical composition of embodiment (HH), wherein        the diglyceride is a mixed or complex diglyceride selected from        the group consisting of glyceryl caproate/caprylate, glyceryl        caproate/caprate, glyceryl caproate/laurate, glyceryl        caproate/myristate, glyceryl caprylate/caprate, glyceryl        caprylate/laurate, glyceryl caprylate/myristate, glyceryl        caprate/laurate, glyceryl caprate/myristate, and glyceryl        laurate/myristate.    -   (JJ) The pharmaceutical composition of embodiment (JJ), wherein        the diglyceride is glyceryl caprylate/caprate.    -   (KK) The pharmaceutical composition of any of embodiments (HH)        through (JJ), wherein the diglyceride comprises from about 5        weight percent to about 10 weight percent of the pharmaceutical        composition.    -   (LL) The pharmaceutical composition of embodiment (KK), wherein        the diglyceride comprises from about 8 to about 9 weight percent        of the pharmaceutical composition.    -   (MM) The pharmaceutical composition of embodiments (I), wherein        the d-α-tocopherol polyethylene glycol succinate derivative has        the structure

-   -   and n is 1-100.    -   (NN) The pharmaceutical composition of embodiment (MM), wherein        n is 1 to 50.    -   (OO) The pharmaceutical composition of embodiment (NN), wherein        n is 1 to 25.    -   (PP) The pharmaceutical composition of embodiment (OO), wherein        n is about 22.    -   (QQ) The pharmaceutical composition of embodiment (MM), wherein        the d-α-tocopherol polyethylene glycol succinate derivative is        TPGS-1000.    -   (RR) The pharmaceutical compositions of any of embodiments (MM)        through (QQ), wherein the d-α-tocopherol polyethylene glycol        succinate derivative comprises from about 0.1 weight percent to        about 5 weight percent of the pharmaceutical composition.    -   (SS) The pharmaceutical composition of embodiment (RR), wherein        the d-α-tocopherol polyethylene glycol succinate derivative        comprises from about 2 weight percent to about 3 weight percent        of the pharmaceutical composition.    -   (TT) The pharmaceutical composition of embodiment (SS), wherein        the d-α-tocopherol polyethylene glycol succinate derivative        comprises about 2.3 weight percent or about 2.4 weight percent        of the pharmaceutical composition.    -   (UU) The pharmaceutical composition of any of the foregoing        embodiments, wherein the pharmaceutical composition provides an        oral bioavailability of at least about 150 percent as measured        by an increase in AUC when compared to a reference product.    -   (VV) The pharmaceutical composition of embodiment (UU), wherein        the reference product is PROMETRIUM.    -   (WW) The pharmaceutical composition of any preceding embodiment,        further comprising a terpene.    -   (XX) The pharmaceutical composition of embodiment (WW), wherein        the terpene is d-limonene.    -   (YY) A method of treating a disease or condition associated with        reduced progesterone levels, the method comprising administering        to a subject in need thereof a pharmaceutical composition        according to any of the preceding embodiments.    -   (ZZ) A method of treating a disease or condition associated with        reduced progesterone levels, the method comprising administering        to a subject in need thereof a pharmaceutical composition of any        of the preceding embodiments.    -   (AAA) The method of embodiment (ZZ), wherein the disease or        condition associated with reduced progesterone levels is        selected from the group consisting of endometrial hyperplasia;        secondary amenorrhea; prevention of preterm birth; and        osteoporosis.    -   (BBB) The method of embodiment (AAA), wherein the disease or        condition associated with reduced progesterone levels is        menopause.    -   (CCC) A method of treating a disease or condition associated        with reduced progesterone levels, the method comprising        administering to a subject in need thereof a pharmaceutical        composition comprising one or more predominantly medium chain        oils and progesterone, wherein the pharmaceutical composition        has an AUC that is at least 150% of the AUC of an equal amount        of a reference product.    -   (DDD) The method of embodiment (CCC), wherein the pharmaceutical        composition has a C_(max) that is at least 150% of the C_(max)        of an equal amount of a reference product    -   (EEE) The pharmaceutical composition of any of the preceding        embodiments, wherein progesterone is the sole active agent.

EXAMPLES

The pharmaceutical composition described herein is now further detailedwith reference to the following examples. These examples are providedfor the purpose of illustration only and the embodiments describedherein should in no way be construed as being limited to these examples.Rather, the embodiments should be construed to encompass any and allvariations which become evident as a result of the teaching providedherein.

Example 1: Pharmaceutical Compositions

Pharmaceutical compositions having the ingredients shown in Table 1 wereprepared by combining the ingredients using standard preparatorytechniques.

TABLE 1 Solubilized Progesterone Fill Formulas (all values presented inmg/g) Pharma. Composition Component A B C D E F G CAPMUL 761.06  723.01 723.01  761.06  834.62  — 751.16  708G CAPMUL 84.56 80.33 80.33 84.56 —834.62  83.46 MCM, NF Ultra High — 42.28 42.28 — — — — Purity d-limonene BHT  0.28  0.28  0.28  0.28 — — — Progesterone 60.13 60.1360.13 60.13 72.64 72.64 72.64 Polysorbate 80 70.47 70.47 46.98 46.9869.55 69.55 69.55 TPGS 1000 23.49 23.49 — — 23.18 23.18 23.18 KOLLIPHOR— — 46.98 46.98 — — — RH 40

Example 2: Particle Size Analysis

Average particle sizes for each of Pharmaceutical Compositions A, B, C,and D as disclosed in Example 1 were measured using a DELSA Nano photoncorrelation spectrometer. Approximately 0.5 g of a given sample wasdiluted with 55 ml of filtered deionized water and the mean size of theresulting particle and the zeta potential was calculated.

TABLE 2 Pharmaceutical Mean size (nm) ± Zeta Potential composition Std.Dev. (mV) A 301.6 ± 164.4 −16.89 B 678.2 ± 698.6 −16.87 C 575.2 ± 604.8−20.63 D 156.3 ± 52.2  −18.37

Example 3: Oral Bioavailability in Rats

Oral bioavailability of the pharmaceutical compositions were assessed inmale Sprague-Dawley rats. According to the protocol, 30 male rats weredivided into 6 groups of 5 rats each. The rats were then treated withone of the pharmaceutical compositions discussed in Example 1(Compositions A, B, C, and D), Pharmaceutical Composition H (anon-micelle forming, fully-solubilized progesterone pharmaceuticalcomposition within the scope of this disclosure described more fully inTable 3), or PROMETRIUM according to the schedule shown in Table 4.

TABLE 3 Pharmaceutical Composition H Component Chemical Name Quantity(mg/g) CAPMUL Glyceryl 846 708 G Caprylate CAPMUL Caprylic/capric 94MCM, NF mono/diglycerides Progesterone API 60

TABLE 4 Study Day Event −4 Animals were transferred to surgery facilityand were group/gang housed. −3 Animals were observed. −2 Animals wereobserved. −1 Animals were fitted with jugular vein catheters (vaporizedisoflurane anesthesia) and treated with analgesics. The animals werefasted for 12 hours starting at 8:00 PM. 0 Gavage capsules were filledwith 20 μL of compound per capsule. Baseline plasma samples werecollected, the animals received compound via capsule gavage, andadditional plasma samples were taken at 10, 20, 40, 60, 90, 120, 180,and 240 minutes post dosing. Frozen plasma samples were shipped on dryice for analysis.

Although PROMETRIUM was dosed in a capsule filled with 20 μL of thePROMETRIUM formulation, the PROMETRIUM capsule contained at least 6times as much progesterone (400 mg/g formulation) as the testpharmaceutical compositions (60 mg/g composition) due to the way inwhich PROMETRIUM is formulated.

The frozen plasma samples were then analyzed and the data plotted. Theresults are shown in FIGS. 1 (linear-linear) and 2 (log-linear). Bothfigures show that test Pharmaceutical Compositions A, C, and D performedbetter than Pharmaceutical Composition H and PROMETRIUM. FIG. 11 showsthe performance of Pharmaceutical Composition D and PROMETRIUM, as bothshown in FIG. 1, in the absence of the other tested formulations.

The means of the PK parameters observed (+/− standard deviation) areshown in Table 5.

TABLE 5 Non-Normalized Progesterone PK Data A B C D H PROMETRIUM Dose3.7 3.7 3.7 3.7 3.7 25 (mg/kg) C_(max) 20.8 ± 12.8 13 ± 9  24.7 ± 11.223.5 ± 15.3 13.1 ± 6.9 6.9 ± 4.0 (ng/mL) t_(max) (hr) 0.467 ± 0.1830.167 ± 0.167  0.4 ± 0.346 0.333 ± 0.204  0.367 ± 0.183  2.2 ± 1.609AUC_(0-t) 27.3 ± 23.0 12.5 ± 9.2  26.2 ± 11.9 24.2 ± 8.8  14.1 ± 7.615.1 ± 8.4  (ng · hr/mL) AUC_(0-∞) 28.0 ± 23.4 14.1 ± 11.1 27.1 ± 11.725.5 ± 8.2  15.6 ± 8.5 18.9 ± 13.6 (ng · hr/mL)

Despite containing significantly less progesterone than PROMETRIUM, eachof the test pharmaceutical compositions provided a higher C_(max)(greater than 10-fold) and AUC_(0-t) (4.5 to 10-fold—except forPharmaceutical Composition H, which showed an AUC similar toPROMETRIUM), when normalized to a standard 1 mg dose than was observedfor PROMETRIUM. Each of the test pharmaceutical compositions had ahigher C_(max) and shorter t_(max) than PROMETRIUM, suggesting morerapid absorption.

In addition, the relative amount of a down-stream metabolite ofprogesterone (allopregnanolone sulfate) was much higher in rats dosedwith PROMETRIUM (AUC approximately 90% of the AUC for progesterone) thanwith the test pharmaceutical compositions (approximately 6-15%).Allopregnolone is believed to be associated with somnolence side effectin humans. In certain embodiments, Pharmaceutical Compositions A, B, C,or D can be administered to reduce or eliminate a somnolence side effectin patients needing progesterone therapy. See, FIGS. 3 and 4.

Each of test pharmaceutical compositions also provided faster onset ofaction than PROMETRIUM by over an hour and a half. In certainembodiments, a faster onset of action demonstrates the improvedbioavailability over currently available hormone formulations. Given thevast difference in progesterone concentration between PROMETRIUM and thedescribed pharmaceutical compositions, these results are highlysurprising and unexpected.

Example 4: Food Effect on Oral Absorption

According to the protocol, 56 male Sprague-Dawley rats were divided into8 groups of 7 rats each. Each group was given one of three testpharmaceutical compositions or PROMETRIUM as set forth in Table 6according to the schedule shown in Table 7. Animals in “Fed” groups werepresented with a pre-weighed amount of food 15 minutes prior toreceiving a given pharmaceutical composition. The food was removed 45minutes after dosing and weighed to calculate average consumption peranimal. Animals in fasted groups received food approximately 4 hoursafter dosing.

TABLE 6 Pharmaceutical Fed/ Group Composition Fasted 1 PROMETRIUM Fasted2 PROMETRIUM Fed 3 D Fasted 4 D Fed 5 A Fasted 6 A Fed 7 C Fasted 8 CFed

TABLE 7 Study Day Event −4 Animals were transferred to surgery facilityand were group/gang housed. −3 Animals were observed. −2 Animals wereobserved. −1 Animals were fitted with jugular vein catheters (vaporizedisoflurane anesthesia) and treated with analgesics. The animals werefasted for 16 hours starting at 4:00 PM. 0 Gavage capsules were filledwith 20 μL of compound per capsule. The Animals were either fed orfasted, as noted above, and given compositions via capsule gavage.Plasma samples were taken at 10, 20, 40, 60, 90, 120, 180, and 240minutes post dosing. Frozen plasma samples were shipped on dry ice foranalysis.

The results of this study are show in FIGS. 7, 8, 9, and 10 and showthat there was no clear food effect on the PK of any of thepharmaceutical compositions, but dose-normalized progesterone exposurefor the test pharmaceutical compositions was approximately 5-fold higherfor C_(max) and 3-fold higher for AUC_(o-t) than for PROMETRIUM.

In certain embodiments, the C_(max) and AUC_(0-t) differences betweenthe test compositions and PROMETRIUM are surprising given thatPROMETRIUM contains about 400 mg progesterone per gram of formulation,whereas the test pharmaceutical compositions contain 60 mg progesteroneper gram of formulation (i.e. about 6 weight percent). In view of thissignificant difference in the amount of available progesterone when bothcompositions were dosed at equal volumes (i.e. 20 μl), a person ofordinary skill in the art would not have predicted that the presentpharmaceutical compositions would enhanced oral bioavailability versusthe reference composition (PROMETRIUM).

The breadth and scope of the present invention should not be limited byany of the above-described exemplary embodiments, but should be definedonly in accordance with the following claims and their equivalents.

All patents, patent applications, and other reference noted orreferenced in this application are hereby incorporated by reference intheir entirety.

What is claimed is:
 1. A pharmaceutical composition for providingenhanced oral bioavailability of progesterone, the pharmaceuticalcomposition comprising: progesterone, a polysorbate, and a medium chainoil, wherein the medium chain oil comprises at least about 50 weightpercent of a predominantly medium chain monoglyceride; and theprogesterone is fully solubilized.
 2. The pharmaceutical composition ofclaim 1, wherein the medium chain oil comprises at least about 70 weightpercent of a predominantly medium chain monoglyceride.
 3. Thepharmaceutical composition of claim 2, wherein the polysorbate isselected from the group consisting of polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 65, and polysorbate
 80. 4. Thepharmaceutical composition of claim 1, wherein the pharmaceuticalcomposition provides an oral bioavailability of at least about 150percent as measured by an increase in AUC when compared to a referenceproduct.
 5. The pharmaceutical composition of claim 1, furthercomprising at least one of a polyoxyethylene hydrogenated castor oil, aD-α-Tocopherol polyethylene glycol succinate derivative, or a terpene.6. The pharmaceutical composition of claim 1, wherein the predominantlymedium chain monoglyceride and the progesterone can be present at aweight ratio of about 10:1 to about 15:1.
 7. The pharmaceuticalcomposition of claim 6, wherein the predominantly medium chainmonoglyceride comprises at least about 90 weight percent of the mediumchain oil.
 8. The pharmaceutical composition of claim 7, wherein thepolysorbate is selected from the group consisting of polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 65, and polysorbate
 80. 9.The pharmaceutical composition of claim 6, wherein the pharmaceuticalcomposition provides an oral bioavailability of at least about 150percent as measured by an increase in AUC when compared to a referenceproduct.
 10. The pharmaceutical composition of claim 6, furthercomprising at least one of a polyoxyethylene hydrogenated castor oil,d-α-tocopherol polyethylene glycol succinate derivative, or a terpene.11. An oral, fully-solubilized progesterone pharmaceutical compositioncomprising: progesterone and a polysorbate in a weight ratio of fromabout 1:2 to about 2:1; and a medium chain oil comprising a mixture ofmedium chain mono- and diglycerides, the medium chain oil not containingmore than about 10 weight percent triglycerides.
 12. The pharmaceuticalcomposition of claim 11, wherein the polysorbate is selected from thegroup consisting of polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 65, and polysorbate
 80. 13. The pharmaceutical compositionof claim 11, wherein the pharmaceutical composition provides an oralbioavailability of at least about 150 percent as measured by an increasein AUC when compared to a reference product.
 14. The pharmaceuticalcomposition of claim 11, further comprising at least one of apolyoxyethylene hydrogenated castor oil, a d-α-tocopherol polyethyleneglycol succinate derivative, or a terpene.
 15. A pharmaceuticalcomposition for providing enhanced oral bioavailability of progesterone,the pharmaceutical composition comprising: progesterone, a polysorbate,and a medium chain oil, wherein the medium chain oil comprises at leastabout 50 weight percent of a first medium chain oil component; and theprogesterone is fully solubilized.
 16. The pharmaceutical composition ofclaim 15, wherein the medium chain oil further comprises a second mediumchain oil component and wherein the first medium chain oil component isa predominantly medium chain monoglyceride and wherein the second mediumchain oil component is a predominantly medium chain diglyceride.
 17. Thepharmaceutical composition of claim 16, wherein the predominantly mediumchain diglyceride is a mixed or complex diglyceride.